Interleukin Structure
Published by Anonymous on 2007/9/30 (5846 reads)
1: Vitam Horm. 2006;74:77-103.
Interleukin-22 and its crystal structure.
Nagem RA, Ferreira Júnior JR, Dumoutier L, Renauld JC, Polikarpov I.
Departamento de Bioquímica e Imunologia, Instituto de Cięncias Biológicas Universidade Federal de Minas Gerais, Avenida Antônio Carlos, 6627 CEP 31270910, Belo Horizonte, MG, Brazil.
Interleukin-22 (IL-22) is a cytokine that regulates the production of acute phase proteins of the immunological response. On binding to its cognate receptor (IL-22R1), which is associated to the interleukin-10 receptor 2 (IL-10R2), IL-22 promotes activation of signal transducer and activator of transcription (STAT) pathway and several other cellular responses. A soluble receptor termed interleukin-22 binding protein (IL-22BP) is also able to bind to IL-22 as a natural protein antagonist, and probably provides systemic regulation of IL-22 activity. This inflammatory response system is analyzed here in terms of its molecular physiology and structural assembly. Three-dimensional (3D) model of IL-22 and structural basis of its interactions with the cognate receptors are discussed.
Publication Types:
Review
PMID: 17027512 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
2: Postepy Hig Med Dosw. 2003;57(6):669-83.
[Interleukin 2 receptor--the structure, function and clinical significance in malignant diseases of adults and children]
[Article in Polish]
Bień E, Balcerska A.
Klinika Pediatrii, Hematologii, Onkologii i Endokrynologii Akademii Medycznej w Gdańsku. ebien@amedec.amg.gda.pl
The paper summarizes the up-to-date knowledge on structure, source, biological function and clinical significance of Interleukin-2 receptor measurements in patients suffering from neoplastic diseases. The authors review the role and clinical usefulness of soluble IL-2R alpha in neoplasms' diagnostics, prognosis and treatment monitoring both in adult patients and in children.
Publication Types:
English Abstract
Review
PMID: 15002163 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
3: Immunogenetics. 2003 Mar;54(12):817-29. Epub 2003 Feb 21.
Genetic variations in the interleukin-12/interleukin-23 receptor (beta1) chain, and implications for IL-12 and IL-23 receptor structure and function.
van de Vosse E, Lichtenauer-Kaligis EG, van Dissel JT, Ottenhoff TH.
Department of Infectious Diseases, Leiden University Medical Center (LUMC), Leiden, The Netherlands.
Cell-mediated immunity (CMI) plays an essential role in human host defense against intracellular bacteria. Type-1 cytokines, particularly gamma interferon (IFN-gamma), interleukin-12 (IL-12), and IL-23, the major cytokines that regulate IFN-gamma production, are essential in CMI. This is illustrated by patients with unusual severe infections caused by poorly pathogenic mycobacteria and Salmonella species, in whom genetic deficiencies have been identified in several key genes in the type-1 cytokine pathway, including IL12RB1, the gene encoding the beta1 chain of the IL-12 and IL-23 receptors. Several mutations in IL12RB1 with deleterious effects on human IL-12R function have been identified, including nonsense and missense mutations. In addition, a number of coding IL12RB1 polymorphisms have been reported. In order to gain more insight into the effect that IL12RB1 mutations and genetic variations can have on IL-12Rbeta1 function, three approaches have been followed. First, we determined the degree of conservation at the variant amino acid positions in IL-12Rbeta1 between different species, using known deleterious mutations, known variations in IL-12Rbeta1, as well as novel coding variations that we have identified at position S74R and R156H. Second, we analyzed the potential impact of these amino acid variations on the three-dimensional structure of the IL-12Rbeta1 protein. Third, we analyzed the putative functions of different IL-12Rbeta1 domains, partly based on their homology with gp130, and analyzed the possible effects of the above amino acid variations on the function of these domains. Based on these analyses, we propose an integrated model of IL-12Rbeta1 structure and function. This significantly enhances our molecular understanding of the human IL-12 and IL-23 systems.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 12671732 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
4: J Interferon Cytokine Res. 2000 Oct;20(10):843-55.
Interleukin-1/Toll receptor family members: receptor structure and signal transduction pathways.
Daun JM, Fenton MJ.
Pulmonary Center, Boston University School of Medicine, Boston, MA 02118, USA.
Interleukin-1 (IL-1) is a central mediator of the inflammatory response. It plays a role in both systemic and local immune responses to invading microbes. There are two receptors (IL-1RI and IL-1RII) that mediate the cellular responses. These receptors belong to a family of receptors based on homologous receptor structure within the intracellular signaling domain. Other family members include the Drosophila protein Toll, the recently discovered mammalian Toll-like receptors (TLR), and the IL-18 receptor. Engagement of these receptors by their diverse ligands results in activation of very similar signal transduction cascades through use of common signaling intermediates. These signal transduction cascades lead to the activation of cellular responses that are known to regulate the innate immune response. Therefore, elucidating the function and redundancy of this receptor family is essential to the understanding of the innate immune response. This review examines each member of this receptor family and emphasizes similarities and potential differences in both receptor structure and signal transduction pathways to further the understanding of this complex receptor family.
Publication Types:
Review
PMID: 11054272 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
5: Int J Mol Med. 1998 Mar;1(3):551-7.
Structure of and signal transduction through interleukin-4 and interleukin-13 receptors (review).
Murata T, Obiri NI, Puri RK.
First Department of Internal Medicine, School of Medicine, Yokohama City University, Yokohama 236, Japan.
We have recently demonstrated that two different forms of IL-4R exist; classical or alternative. The classical IL-4R is predominantly expressed in hematopoietic cells and consist of IL-4R and IL-2Rgammac (gammac) chains. On the other hand, alternative form of IL-4R is predominantly expressed in non-hematopoietic cells and consists of IL-4R and IL-13Ralpha' chains. Moreover, the alternative form of IL-4R is also utilized as a functional component IL-13R complex. It has been shown that the phosphorylation and activation of JAK3 tyrosine kinase is crucial for IL-4 activation of STAT6 in hematopoietic cells. However, we have recently demonstrated that non-hematopoietic cells lack JAK3 expression. We also demonstrated that in these cells, STAT6 activation is mediated through JAK1 and JAK2 tyrosine kinases instead. Furthermore, our results show that IL-4 and IL-13 signals are transmitted through the alternative form of IL-4R in these cells. Thus, major differences exist between hematopoietic and non-hematopoietic cells with regard to structure and signal transduction through IL-4R and IL-13R systems.
Publication Types:
Review
PMID: 9852261 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
6: Int Rev Immunol. 1998;16(3-4):345-64.
Interleukin 9 and its receptor: an overview of structure and function.
Demoulin JB, Renauld JC.
Ludwig Institute for Cancer Research and Experimental Medicine Unit, Catholic University of Louvain, Brussels, Belgium.
Interleukin-9 (IL-9) is a multifunctional cytokine produced by activated TH2 clones in vitro and during TH2-like T cell responses in vivo. Although IL-9 was initially described as a T cell growth factor, its role in T cell responses is still unclear. While freshly isolated normal T cells do not respond to IL-9, this cytokine induces the proliferation of murine T cell lymphomas in vitro, and in vivo overexpression of IL-9 results in the development of thymic lymphomas. In the human, the existence of an IL-9 mediated autocrine loop has been suggested for some malignancies such as Hodgkin's disease. Various observations indicate that IL-9 is actively involved in mast cells responses by inducing the proliferation and differentiation of these cells. Other potential biological targets for IL-9 include B lymphocytes, and hematopoietic progenitors, for which higher responses were observed with foetal or transformed cells as compared to normal adult progenitors. The IL-9 receptor is a member of the hemopoietin receptor superfamily and interacts with the gamma chain of the IL-2 receptor for signaling. Signal transduction studies have stressed the role of the Jak-STAT pathway in various IL-9 bioactivities, whereas the 4PS/IRS2 adaptor protein might also play a significant role in IL-9 signaling.
Publication Types:
Review
PMID: 9505195 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
7: Protein Sci. 1997 May;6(5):929-55.
Interleukin-6: structure-function relationships.
Simpson RJ, Hammacher A, Smith DK, Matthews JM, Ward LD.
Joint Protein Structure Laboratory, Ludwig Institute for Cancer Research, (Melbourne Tumour Biology Branch), Parkville, Victoria, Australia. simpson@licre.ludwig.edu.au
Interleukin-6 (IL-6) is a multifunctional cytokine that plays a central role in host defense due to its wide range of immune and hematopoietic activities and its potent ability to induce the acute phase response. Overexpression of IL-6 has been implicated in the pathology of a number of diseases including multiple myeloma, rheumatoid arthritis, Castleman's disease, psoriasis, and post-menopausal osteoporosis. Hence, selective antagonists of IL-6 action may offer therapeutic benefits. IL-6 is a member of the family of cytokines that includes interleukin-11, leukemia inhibitory factor, oncostatin M, cardiotrophin-1, and ciliary neurotrophic factor. Like the other members of this family, IL-6 induces growth or differentiation via a receptor-system that involves a specific receptor and the use of a shared signaling subunit, gp130. Identification of the regions of IL-6 that are involved in the interactions with the IL-6 receptor, and gp130 is an important first step in the rational manipulation of the effects of this cytokine for therapeutic benefit. In this review, we focus on the sites on IL-6 which interact with its low-affinity specific receptor, the IL-6 receptor, and the high-affinity converter gp130. A tentative model for the IL-6 hexameric receptor ligand complex is presented and discussed with respect to the mechanism of action of the other members of the IL-6 family of cytokines.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 9144766 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
8: Vitam Horm. 1997;53:27-63.
Structure and function of interleukin-1 beta converting enzyme.
Tocci MJ.
Department of Molecular Immunology, Merch Research Laboratories, Rahway, New Jersey 07065, USA.
An overwhelming body of evidence has shown that IL-1 beta is a major mediator of inflammatory disease (Tocci and Schmidt, 1996). The discovery of ICE, a unique processing enzyme involved in the production of active IL-1 beta, has provided a new approach to specifically block the production of this potent cytokine. Consequently, the discovery and development of inhibitors against the enzyme could hold great promise therapeutically. Potent inhibitors of the enzyme would be useful in the treatment of a number of important inflammatory diseases and potentially in the management of leukemia (Arend, 1993b; Estrov and Talpaz, 1996). A number of key questions must be answered before the therapeutic potential of such inhibitors can be realized. The development of a pharmaceutically acceptable cysteine proteinase inhibitor will almost certainly involve new chemical strategies gauged at safely inactivating the enzyme. For such inhibitors, it will be necessary to achieve selectivity for ICE from among the growing number of ICE family members while retaining potency. It will also be important to establish the level of inhibition of IL-1 beta required to achieve therapeutic efficacy. The studies comparing IL-1 beta- and ICE-deficient mice suggest that complete abrogation of IL-1 beta is required to achieve efficacy in models of inflammation. It is not known if this is the case in humans. Understanding the source of the residual IL-1 beta produced in ICE-deficient mice will be important in order to ascertain if a similar mechanism could generate active IL-1 beta in patients receiving if a ICE inhibitor. As for ICE itself, a number of formidable questions remain regarding its regulation and mechanism of activation. Answering these questions experimentally will present a major challenge due to the extremely low levels of enzyme present in cells. Studies on other family members may provide easier access to some of these questions and provide clues that can be applied to ICE. The components of the pathway involved in IL-1 trafficking and secretion are unknown, as are the mechanisms of ICE activation and regulation. Clearly other cellular proteins that have yet to be discovered will be involved in each of these processes, opening up new avenues of research in this field.
Publication Types:
Review
PMID: 9197177 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
9: Ann N Y Acad Sci. 1995 Jul 21;762:222-36; discussion 236-7.
Membrane-bound and soluble interleukin-6 receptor: studies on structure, regulation of expression, and signal transduction.
Heinrich PC, Graeve L, Rose-John S, Schneider-Mergener J, Dittrich E, Erren A, Gerhartz C, Hemann U, Lütticken C, Wegenka U, et al.
Institut für Biochemie, RWTH Aachen, Germany.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 7545364 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
10: Cancer Treat Res. 1995;80:143-85.
Structure and function of interleukin-4 and its receptor.
Puri RK.
Laboratory of Molecular Tumor Biology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA.
Publication Types:
Review
PMID: 8821577 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
11: Acta Haematol Pol. 1995;26(3):257-62.
[Interleukin 2 receptor (Il-2): structure and function]
[Article in Polish]
Dmoszyńska A, Roliński J.
Kliniki Hematologii AM w Lublinie.
Interleukin 2 and its receptor play a crucial role in the growth and differentiation of many cells such as lymphocytes T and B, NK cells, macrophages and monocytes. Il-2 receptor (Il-2R) is involved in Il-2 induced cellular signalling. We discuss the Il-2R structure, function of three distinct subunits and the complex pathways that link the cell surface receptor to the nuclear proto-oncogene production.
Publication Types:
English Abstract
Review
PMID: 8525770 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
12: Agents Actions Suppl. 1995;46:23-34.
Structure/function analysis of human interleukin 5 and its receptor.
Tavernier J, Cornelis S, Devos R, Guisez Y, Plaetinck G, Van der Heyden J.
Roche Research Gent, Belgium.
We have performed a detailed structure-function analysis of human interleukin 5 (hIL5) and its receptor. By testing a hIL5 mutant panel in a solid phase binding assay and a proliferation assay using hIL5 dependent cell-lines, areas on hIL5 involved in either the receptor alpha-subunit interaction or in receptor activation were identified. Epitope mapping data of a neutralizing and a non-neutralizing monoclonal antibody were in agreement with the mutant analysis. hIL5 binding areas on the IL5R alpha-subunit were identified by interspecies chimaera analysis. Finally, hIL5 mutants with reduced receptor activation potential have antagonistic properties.
Publication Types:
Review
PMID: 7610988 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
13: Res Immunol. 1993 Oct;144(8):590-6.
Characterization of the interleukin 4 receptor. Structure and signal transduction pathways.
Keegan AD, Wang LM, Paul WE, Pierce JH.
Laboratory of Immunology, NIAID NIH, Bethesda, MD 20892.
Publication Types:
Review
PMID: 8303078 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
14: Cancer Invest. 1993;11(5):609-23.
Interleukin-3: structure and function.
Lindemann A, Mertelsmann R.
Department of Medicine 1, University of Freiburg, Germany.
Publication Types:
Review
PMID: 8402229 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
15: Nippon Rinsho. 1992 Aug;50(8):1833-9.
[Function, molecular structure and gene expression of interleukin-11 (IL-11/AGIF)]
[Article in Japanese]
Kawashima I, Ohsumi J, Miyadai K, Takiguchi Y.
Interleukin-11 (IL-11) is a novel cytokine that was identified in a medium conditioned by the primate bone marrow-derived stromal cell line PU-34. It was originally identified as a growth factor for the IL-6-dependent plasmacytoma cell line T1165. Adipogenesis inhibitory factor (AGIF) was cloned from the human bone marrow-derived cell line KM-102. The AGIF cDNA sequence was revealed to be identical to that of the IL-11 cDNA. AGIF inhibits the process of adipogenesis of the bone marrow-derived preadipocyte cell line H-1/A. Other biological activities of IL-11/AGIF, megakaryocytopoiesis, stem-cell proliferation, hepatic acute phase responses and antigen-specific antibody responses are also summarized.
Publication Types:
English Abstract
Review
PMID: 1433976 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
16: Nippon Rinsho. 1992 Aug;50(8):1827-32.
[Function, molecular structure and gene expression regulation of interleukin-10 (IL-10)]
[Article in Japanese]
Nakahata T, Tsuji K.
Department of Pediatrics, Shinshu University School of Medicine.
Interleukin-10 has a variety of biological activities. Murine interleukin-10 inhibits cytokine production by Th2 cells in the presence of macrophages, enhances T cell proliferation, sustains the viability of B cells in vitro, induces class II MHC antigen expression on B cells, enhances mast cell proliferation in the presence of IL-3 and/or IL-4, and inhibits cytokine production by macrophages. Human interleukin-10 inhibits cytokine production by human T cells and reduces antigen-specific human T cell proliferation by downregulation of class II MHC antigen expression on monocytes. cDNA clones encoding murine and human interleukin-10 exhibit a strong homology to BCRFI in Epstein-Barr virus. BCRFI conserves only a part of interleukin-10 activities.
Publication Types:
English Abstract
Review
PMID: 1433975 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
17: Nippon Rinsho. 1992 Aug;50(8):1821-6.
[Function, molecular structure and gene expression regulation of interleukin 9 (IL-9)]
[Article in Japanese]
Sonoda Y.
Department of Hygiene, Kyoto Prefectural University of Medicine.
Interleukin-9 (IL-9)/P40 is a recently reported murine growth factor for helper T-cell clones. It is produced by ConA stimulated CD4+ T-cells or several T-cell lines such as TUC 2.15 derived from C57Bl/6 mouse. In the murine system, IL-9/P40 directly supported proliferation of mucosal type mast cells, and also induced erythroid burst formation, indirectly. On the other hand, human IL-9, which is a homologue to murine P40, was cloned from a cDNA library prepared with mRNA isolated from PHA-induced T-cell line (C5MJ2). Analysis of the sequence of cDNA revealed a striking similarity between murine and human IL-9/P40. Human IL-9 supported formation of a subpopulation of erythroid bursts that are responsive to IL-3. In this communication, identification, cloning of cDNA, and biological activities of murine and human IL-9/P40 are discussed.
Publication Types:
English Abstract
Research Support, Non-U.S. Gov't
Review
PMID: 1433974 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
18: Nippon Rinsho. 1992 Aug;50(8):1769-75.
[Function, molecular structure and gene expression of interleukin-1]
[Article in Japanese]
Kasahara T, Kuno K, Matsushima K.
Department of Medical Biology and Parasitology, Jichi Medical School.
Recent cloning of human and murine IL-1 receptor (IL-1R) has revealed that there are at least two type of IL-1R: type I IL-1R is detected on T cells and fibroblasts and consists of 552 AAs with a cytoplasmic domain of 213 AAs, while type II is detected on B cells and monocytic cell lines and consists of 398 AAs with a short stretch intracytoplasmic domain of 29 AAs. Extracytoplasmic portion of IL-1R has some homology with vaccinia virus B15 Ag or fibroblast protein ST-2, while cytoplasmic portion has considerable similarity with Drosophila toll gene. By transfecting murine type I IL-1R cDNA into a human Jurkat cell line, structural and functional potion required for the IL-1 signal transduction is determined. At least broad portion of cytoplasmic domain including 364-474 AAs from N-terminus are found to be essential, while PKC acceptor site (Ser-431 and Ser-509), and PKA acceptor site (Ser-528) are not essential for the IL-8 gene expression.
Publication Types:
English Abstract
Review
PMID: 1433966 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
19: Chem Immunol. 1992;51:107-34.
The interleukin-4 receptor: structure, function, and signal transduction.
Beckmann MP, Cosman D, Fanslow W, Maliszewski CR, Lyman SD.
Immunex Corporation, Seattle, Wash.
Publication Types:
Review
PMID: 1567539 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
20: Proteins. 1992 Jan;12(1):10-23.
Functional implications of interleukin-1 beta based on the three-dimensional structure.
Veerapandian B, Gilliland GL, Raag R, Svensson AL, Masui Y, Hirai Y, Poulos TL.
Center for Advanced Research in Biotechnology, University of Maryland, Rockville.
The molecular structure of interleukin-1 beta, a hormone-like cytokine with roles in several disease processes, has been determined at 2.0 A resolution and refined to a crystallographic R-factor of 0.19. The framework of this molecule consists of 12 antiparallel beta-strands exhibiting pseudo-3-fold symmetry. Six of the strands make up a beta-barrel with polar residues concentrated at either end. Analysis of the three-dimensional structure, together with results from site-directed mutagenesis and biochemical and immunological studies, suggest that the core of the beta-barrel plays an important functional role. A large patch of charged residues on one end of the barrel is proposed as the binding surface with which IL-1 interacts with its receptor.
Publication Types:
Review
PMID: 1553379 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
21: Ciba Found Symp. 1992;167:47-62; discussion 62-7.
Regulation of expression of the interleukin 6 gene: structure and function of the transcription factor NF-IL6.
Akira S, Isshiki H, Nakajima T, Kinoshita S, Nishio Y, Natsuka S, Kishimoto T.
Institute for Molecular and Cellular Biology, Osaka University, Japan.
The interleukin 6 (IL-6) promoter is rapidly and transiently activated by other cytokines, including IL-1 and tumour necrosis factor (TNF), as well as by phorbol esters and cyclic AMP agonists. Studies using promoter mutants suggested that an IL-1-responsive element mapped within the -180 to -123 region of the IL-6 promoter. A nuclear factor (NF-IL6) that recognized a unique sequence containing an inverted repeat, ACATTGCACAATCT, was identified within the region. Direct cloning of the human NF-IL6 revealed its similarity to C/EBP, a liver- and adipose tissue-specific transcription factor. C/EBP and NF-IL6 recognize the same nucleotide sequence, but exhibit distinct patterns of expression. NF-IL6 is expressed at a low level in normal tissues, but is rapidly and drastically induced by bacterial lipopolysaccharide (LPS) or inflammatory cytokines such as IL-1, TNF and IL-6. Recently, NF-IL6 has been shown to be identical to IL-6DBP, the DNA-binding protein which is responsible for IL-6-mediated induction of several acute-phase proteins. Evidence that NF-IL6 DNA-binding activity is increased after IL-6 stimulation without increased NF-IL6 protein synthesis demonstrates the importance of post-translational modification. There are some results indicating that phosphorylation is involved in transcriptional and binding activities of NF-IL6. Taken together, these findings indicate that NF-IL6 may be an important transcription factor on the signal transduction pathways of IL-1 and IL-6.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 1385054 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
22: J Invest Dermatol. 1990 Jun;94(6 Suppl):27S-32S.
Interleukin-2 and the IL-2 receptor: new insights into structure and function.
Kuziel WA, Greene WC.
Howard Hughes Medical Institute, Department of Medicine, Durham, North Carolina.
Interleukin-2 (IL-2) was originally identified in 1976 as a growth factor for T lymphocytes. Since that time it has become an important mediator of immune function through its effects on the growth, development, and activity of T and B lymphocytes, natural killer cells, and lymphokine-activated killer cells. Only cells that bear a specific receptor for IL-2 respond to its immunoregulatory effects. Of all the lymphokine-receptor systems in immunology, perhaps most is known about the structure, function, and binding properties of IL-2 and its cognate receptor. There are two distinct, membrane-associated IL-2 binding components in the high-affinity IL-2 receptor: an alpha subunit and a beta subunit, which associate in a non-covalent manner. Each of these polypeptides can occur on the cell surface in the absence of the other and bind IL-2, although with only low or intermediate affinity relative to the high-affinity receptor complex. The primary structure of each chain has now been deduced from full-length cDNA. The rapid rate of association between IL-2 and the IL-2R alpha subunit is important in the formation of high-affinity binding sites, and the inducibility of the alpha gene contributes to the highly regulated and transient display of high-affinity IL-2R. The IL-2R beta chain controls the slow dissociation rate of IL-2 from the high-affinity receptor. Also, IL-2R beta appears centrally involved in internalization of IL-2 and signal transduction, functions mediated presumably through its long intracytoplasmic domain. However, the actual mechanism of signal transduction in the IL-2/IL-2R system remains undefined. IL-2R beta is a member of a novel family of cytokine-receptor proteins that includes receptors for IL-4, IL-6, and erythropoietin.
Publication Types:
Review
PMID: 1693645 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
23: Philos Trans R Soc Lond B Biol Sci. 1990 Mar 12;327(1239):187-92.
Structure, function, and regulation of the interleukin-2 receptor and identification of a novel immune activation gene.
Leonard WJ, Gnarra JR, Napolitano M, Sharon M.
Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892.
This chapter is divided into two sections, the first dealing with a novel immune activation gene, denoted Act-2. This gene encodes a secreted protein that may represent a new cytokine. The Act-2 protein shares significant homology with proteins in two related families of small secreted proteins. Act-2 is rapidly synthesized by activated T cells, B cells and monocytes. The second section deals with interleukin-2 receptors. These receptors are now known to be comprised of three distinct classes of receptors, formed by various combinations of two IL-2 binding proteins, the alpha and beta chains. The low-affinity receptors contain alpha, but not beta chains; the intermediate-affinity receptors contain beta, but not alpha chains, and the high-affinity receptors contain both alpha and beta chains. The beta chain appears to be tyrosine phosphorylated. We discuss evidence for the existence of another protein of relative molecular mass 100,000, which appears to be a subunit of at least the high-affinity receptor.
Publication Types:
Review
PMID: 1969658 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
24: Semin Immunol. 1990 Mar;2(2):119-28.
The human interleukin-2 receptor: insights into subunit structure and growth signal transduction.
Fung MR, Greene WC.
Howard Hughes Medical Institute, Department of Medicine and Microbiology-Immunology, Duke University Medical Center, Durham, NC 27710.
Lymphokine-dependent T cell proliferation is regulated in part by the cell surface expression of high affinity interleukin-2 receptors (IL-2R). The functional, high affinity form of the IL-2 receptor is comprised of two ligand binding components, IL-2R alpha (Tac, p55) and IL-2R beta (p70/75). In the absence of the other subunit, IL-2R alpha and IL-2R beta bind ligand with only low or intermediate affinity, respectively. The inducible and transient expression of IL-2R alpha regulates the display of high affinity receptors, while IL-2R beta appears to contribute importantly to growth signal transduction. Although the primary structure of both receptor chains has now been elucidated, the mechanism of growth signal transduction through the high affinity IL-2R remains undefined. Of note, IL-2R beta belongs to a novel family of cytokine receptors including the binding proteins for IL-3, IL-4, IL-6, erythropoietin, and granulocyte-macrophage colony-stimulating factor. These various receptors may well utilize a common intracellular signalling pathway.
Publication Types:
Comparative Study
Research Support, Non-U.S. Gov't
Review
PMID: 2129904 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
25: Prog Clin Biol Res. 1990;352:179-87.
Structure and function of interleukin-2 receptors.
Leonard WJ, Sharon M, Gnarra JR.
Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892.
Publication Types:
Review
PMID: 2205861 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
26: Prog Growth Factor Res. 1990;2(4):193-205.
Interleukin-1 receptor antagonist: discovery, structure and properties.
Arend WP.
Department of Medicine, University of Colorado Health Sciences Center, Denver 80262.
Interleukin-1 receptor antagonist (IL-1ra) is a recently-described member of the IL-1 family. This unique human protein has 30% amino acid sequence homology to IL-1 beta and binds to human types I and II IL-1 receptors without apparent cellular activation. IL-1ra blocks the in vitro stimulatory effects of IL-1 on thymocytes, fibroblasts, endothelial cells and bone cells. In addition, IL-1ra is a potent inhibitor of the inflammatory effects of IL-1 in vivo. IL-1ra represents the first naturally-occurring cytokine inhibitor and may be important in modulating IL-1 effects in both normal and abnormal physiology.
Publication Types:
Review
PMID: 2151936 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
27: Ann Ist Super Sanita. 1990;26(3-4):273-82.
Human interleukin 1: structure-function relationship.
Boraschi D, Tagliabue A.
Laboratorio di Immunofarmacologia, Centro di Ricerche Sclavo, Siena, Italy.
The pleiotropic activities of IL-1 have fostered a series of studies on the structure-function relationship in these proteins. The most extensively studied in this respect has been human IL-1 beta. It has been shown that enzymatic cleavage of the precursor protein to generate the mature polypeptide appears necessary for its full biological activity. The almost complete integrity of the mature IL-1 beta protein is also required for its ability to bind to the receptor and trigger cellular functions. However, by the use of monoclonal antibodies and recombinant or synthetic peptides, it has been possible to map some IL-1 beta regions important for different activities. Both N-terminal and C-terminal fragments are important for receptor binding. A domain around amino acids 187-204 is apparently involved in the hyperalgesic effects of IL-1 beta. Finally, the fragment in position 163-171 appears to be responsible for a restricted series of the IL-1 beta activities, mainly directed to the immune system, although irrelevant for inflammation-related effects and unable of binding to the IL-1R. The understanding of the structure-function relationship of IL-1 obtained so far is expected to give rise within a short time to a new generation of synthetic and/or recombinant derivatives to be experimented for clinical purposes.
Publication Types:
Review
PMID: 2091500 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
28: Biotherapy. 1989;1(4):377-89.
Structure-function relationship of interleukin-1 giving new insights for its therapeutic potential.
Boraschi D, Tagliabue A.
Laboratory of Immunopharmacology, Sclavo Research Center, Siena, Italy.
The pleiotropic activities of IL-1 have fostered a series of studies on the structure-function relationship in these proteins. In fact, the attempt to dissociate different biological functions of IL-1 should simplify its therapeutic use. About human IL-1 beta, which has been more extensively studied in this respect, enzymatic cleavage of the precursor protein to generate the mature polypeptide appears necessary for its full biological activity. The almost complete integrity of the mature IL-1 beta protein is also required for its ability to bind to the receptor and trigger cellular functions. However, by the use of monoclonal antibodies and recombinant or synthetic peptides, it has been possible to map some IL-1 beta regions important for different activities. Both N-terminal and C-terminal fragments are important for receptor binding. A domain around amino acids 187-204 is apparently involved in the hyperalgesic effects of IL-1 beta. Finally, the fragment in position 163-171 appears to be responsible for a restricted series of the IL-1 beta activities, mainly directed to the immune system, although irrelevant for inflammation-related effects and unable of binding to the IL-1R. It is thus possible, within the sequence of a cytokine, to isolate selectively active domains. This will give us new tools for new therapeutic approaches. Thus, IL-1 might be the prototype of a new generation of cytokines developed with the goal of stimulating specific biological activities without activating the cascade effects which are typical for many cytokines.
Publication Types:
Review
PMID: 2701651 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
29: Sb Ved Pr Lek Fak Karlovy Univerzity Hradci Kralove Suppl. 1989;32(4):397-411.
[Interleukin 2. Biochemical aspects of structure and function. Review]
[Article in Czech]
Kovárová H, Stulík J, Macela A.
Ustav lékarské biochemie, II. katedry interních oborů, farmakologie a lékarské biochemie.
During the last several years, the important progress has been achieved in studying activation and proliferation processes altogether with differentiation of mononuclear cells and regulatory course of immune response. In addition to molecular biology, also the biochemical characterization of interleukins, mainly Interleukin 2 (IL 2), is of a substantial import. IL 2 is actionning as an amplificator of T and B immune cellular reactions, and it influences the production of lymphokines, i.e., gamma interferon as well as participates in antitumorous immunity. IL 2 belongs to the range of products being secreted by T lymphocytes following the specific antigenic or polyclonal mitogenic simulation of cells. It can be classed as a growth factor of cells and regulatory factor of immune responsiveness. The human IL 2 was isolated as a protein with Mr 16 kD. On the basis of complementary DNA, the molecular weight has been determined for IL 2 as 15.4 kD. The IL 2-related human gen is localized on 4th chromosome and the product of the respective gen is a protein composed of 133 amino acids. This very protein undergoes glycosylation on the 3d position having alpha-helicoid conformation. The murine IL 2 occurs rather as a dimer composed of two protein chains with Mr 16-18 kD. Variable degrees of glycosylation involve the heterogeneity and pI differences in isolated forms of IL 2. Actions of IL2 are triggered by its interaction with specific receptor, which appears on the T cells no sooner as they are activated by the antigen or mitogen. Following the IL 2 with receptor interaction, the hydrolysis of phosphatidylinositolphosphate occurs intracellularly as well as activation of proteinkinase C and a track of other biochemical reactions non-elucidated till now, which lead up to the transcription regulation of genes and transfer of mitotic apparatus from G1 into S phase of cellular cycle and of division of cells.
Publication Types:
English Abstract
Review
PMID: 2701131 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
30: Adv Exp Med Biol. 1989;254:61-5.
Structure-function relationships for high and low-affinity interleukin 2 receptors.
Robb RJ.
Medical Products Department E. I. du Pont de Nemours & Co. Glenolden, PA 19036.
Publication Types:
Review
PMID: 2683608 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
31: Year Immunol. 1989;5:46-58.
The human interleukin-2 receptor. Structure and molecular regulation.
Leonard WJ, Sharon M, Cross SL.
Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, Bethesda, Md.
Publication Types:
Review
PMID: 2652930 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
32: Year Immunol. 1989;5:126-59.
Interleukin-4: molecular structure and biochemical characteristics, biological function, and receptor expression.
Ohara J.
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, Bethesda, Md.
Publication Types:
Review
PMID: 2652925 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
33: Tanpakushitsu Kakusan Koso. 1988 Sep;33(11):1793-802.
[Interleukin-1: a multifunctional molecule in inflammation and immune response--its structure and function in defence system]
[Article in Japanese]
Goto F.
Publication Types:
Review
PMID: 2977227 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
34: Immunol Rev. 1988 Feb;102:189-212.
Structure and function of interleukin 4 and 5.
Sideras P, Noma T, Honjo T.
Department of Medical Chemistry, Kyoto University Faculty of Medicine, Japan.
Publication Types:
Review
PMID: 3284814 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
35: Ann N Y Acad Sci. 1988;546:116-21.
The human interleukin-2 receptor. Recent studies of structure and regulation.
Greene WC, Böhnlein E, Siekevitz M, Franza BR, Lowenthal J.
Howard Hughes Medical Institute, Duke University Medical Center, Durham, North Carolina 27710.
Publication Types:
Review
PMID: 3073691 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
36: Recent Prog Horm Res. 1988;44:141-55.
New insights into the structure of high-affinity interleukin-2 receptors.
Greene WC, Wano YJ, Dukovich M.
Publication Types:
Review
PMID: 3064206 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
37: Blood Rev. 1987 Dec;1(4):254-66.
Interleukin 2 and its receptor: structure, function and therapeutic potential.
Malkovský M, Sondel PM.
MRC Clinical Research Centre, Harrow, Middlesex, UK.
In this review, salient molecular, biochemical and functional features of human interleukin 2 (IL-2), its membrane receptor, and its clinical relevance are outlined. We also describe experimental systems, where observed biological or pharmacological effects of IL-2 could be applied to corresponding clinical situations. In particular, IL-2 has been intensively studied in the context of cancer therapy. We discuss the rationale for the use of IL-2 in cancer treatment and our experience in this area. A better understanding of the IL-2 system and, specifically, the nature of signals transduced through it will allow us to manipulate the immune response in a variety of different ways, resulting in new approaches to investigation of immune responsiveness in general. This may have a profound impact on clinical medicine.
Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 3332110 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
38: Clin Res. 1987 Sep;35(5):439-50.
The human interleukin-2 receptor: a molecular and biochemical analysis of structure and function.
Greene WC.
Publication Types:
Review
PMID: 2889557 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
39: Immunol Rev. 1986 Aug;92:81-101.
The murine interleukin-2 receptor: biochemical structure and regulation of expression.
Malek TR, Ashwell JD, Germain RN, Shevach EM, Miller J.
Publication Types:
Review
PMID: 3091485 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
40: Immunol Rev. 1986 Aug;92:29-48.
The human interleukin-2 receptor: analysis of structure and function.
Greene WC, Depper JM, Krönke M, Leonard WJ.
Considerable information presently exists regarding the molecular, biochemical, and biological features of the human IL-2 receptor. The IL-2 receptor protein, multiple receptor mRNAs, and a single structural gene have now been identified. The important role of this receptor in normal T-cell growth is well established and its potential participation in B-cell growth and differentiation appreciated. The availability of cloned gene products for both the IL-2 receptor and IL-2 may permit the future development of novel biological agents capable of either augmenting or blunting the T-cell immune response. The intriguing interrelationship of HTLV-I and -II infection and altered IL-2 receptor expression is now being unraveled. However, the structural difference in high and low affinity receptors as well as the mechanism by which signals for T-cell growth are propagated through the high affinity receptor remain dominant, unanswered questions in the field.
Publication Types:
Review
PMID: 3091481 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
41: Immunol Rev. 1986 Aug;92:103-20.
Structure and function of the interleukin 2 receptor: affinity conversion model.
Shimizu A, Kondo S, Sabe H, Ishida N, Honjo T.
We cloned cDNAs of the human and mouse IL-2 receptors. Comparison of their structures allowed us to identify several conserved regions localized to exons 2 and 4, the cytoplasmic portion and the transmembrane portion. These regions might be important for the functions of the IL-2 receptor. The human IL-2 receptor, which was expressed on an IL-2-dependent murine T-cell line, CTLL-2, by cDNA transfection, was shown to be functionally active by blocking the endogenous mouse IL-2 receptor with monoclonal antibodies. On the other hand, the human IL-2 receptors expressed on non-lymphoid cells were functionally inactive. They were unable to mediate the growth signal, were of low affinity species and aberrant in internalization. We postulated that the dysfunction of the IL-2 receptors in non-lymphoid cells would be due to the absence of the putative converter protein which is expressed specifically in lymphoid cells. Since the human IL-2 receptor is active in the murine T cell, the converter may interact with the receptor at the portions conserved between man and mouse. We proposed the affinity conversion model that explained the high affinity state of the receptor by the ternary complex formation between IL-2, the IL-2 receptor and the converter.
Publication Types:
Comparative Study
Research Support, Non-U.S. Gov't
Review
PMID: 3091479 [PubMed - indexed for MEDLINE]
Interleukin-22 and its crystal structure.
Nagem RA, Ferreira Júnior JR, Dumoutier L, Renauld JC, Polikarpov I.
Departamento de Bioquímica e Imunologia, Instituto de Cięncias Biológicas Universidade Federal de Minas Gerais, Avenida Antônio Carlos, 6627 CEP 31270910, Belo Horizonte, MG, Brazil.
Interleukin-22 (IL-22) is a cytokine that regulates the production of acute phase proteins of the immunological response. On binding to its cognate receptor (IL-22R1), which is associated to the interleukin-10 receptor 2 (IL-10R2), IL-22 promotes activation of signal transducer and activator of transcription (STAT) pathway and several other cellular responses. A soluble receptor termed interleukin-22 binding protein (IL-22BP) is also able to bind to IL-22 as a natural protein antagonist, and probably provides systemic regulation of IL-22 activity. This inflammatory response system is analyzed here in terms of its molecular physiology and structural assembly. Three-dimensional (3D) model of IL-22 and structural basis of its interactions with the cognate receptors are discussed.
Publication Types:
Review
PMID: 17027512 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
2: Postepy Hig Med Dosw. 2003;57(6):669-83.
[Interleukin 2 receptor--the structure, function and clinical significance in malignant diseases of adults and children]
[Article in Polish]
Bień E, Balcerska A.
Klinika Pediatrii, Hematologii, Onkologii i Endokrynologii Akademii Medycznej w Gdańsku. ebien@amedec.amg.gda.pl
The paper summarizes the up-to-date knowledge on structure, source, biological function and clinical significance of Interleukin-2 receptor measurements in patients suffering from neoplastic diseases. The authors review the role and clinical usefulness of soluble IL-2R alpha in neoplasms' diagnostics, prognosis and treatment monitoring both in adult patients and in children.
Publication Types:
English Abstract
Review
PMID: 15002163 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
3: Immunogenetics. 2003 Mar;54(12):817-29. Epub 2003 Feb 21.
Genetic variations in the interleukin-12/interleukin-23 receptor (beta1) chain, and implications for IL-12 and IL-23 receptor structure and function.
van de Vosse E, Lichtenauer-Kaligis EG, van Dissel JT, Ottenhoff TH.
Department of Infectious Diseases, Leiden University Medical Center (LUMC), Leiden, The Netherlands.
Cell-mediated immunity (CMI) plays an essential role in human host defense against intracellular bacteria. Type-1 cytokines, particularly gamma interferon (IFN-gamma), interleukin-12 (IL-12), and IL-23, the major cytokines that regulate IFN-gamma production, are essential in CMI. This is illustrated by patients with unusual severe infections caused by poorly pathogenic mycobacteria and Salmonella species, in whom genetic deficiencies have been identified in several key genes in the type-1 cytokine pathway, including IL12RB1, the gene encoding the beta1 chain of the IL-12 and IL-23 receptors. Several mutations in IL12RB1 with deleterious effects on human IL-12R function have been identified, including nonsense and missense mutations. In addition, a number of coding IL12RB1 polymorphisms have been reported. In order to gain more insight into the effect that IL12RB1 mutations and genetic variations can have on IL-12Rbeta1 function, three approaches have been followed. First, we determined the degree of conservation at the variant amino acid positions in IL-12Rbeta1 between different species, using known deleterious mutations, known variations in IL-12Rbeta1, as well as novel coding variations that we have identified at position S74R and R156H. Second, we analyzed the potential impact of these amino acid variations on the three-dimensional structure of the IL-12Rbeta1 protein. Third, we analyzed the putative functions of different IL-12Rbeta1 domains, partly based on their homology with gp130, and analyzed the possible effects of the above amino acid variations on the function of these domains. Based on these analyses, we propose an integrated model of IL-12Rbeta1 structure and function. This significantly enhances our molecular understanding of the human IL-12 and IL-23 systems.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 12671732 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
4: J Interferon Cytokine Res. 2000 Oct;20(10):843-55.
Interleukin-1/Toll receptor family members: receptor structure and signal transduction pathways.
Daun JM, Fenton MJ.
Pulmonary Center, Boston University School of Medicine, Boston, MA 02118, USA.
Interleukin-1 (IL-1) is a central mediator of the inflammatory response. It plays a role in both systemic and local immune responses to invading microbes. There are two receptors (IL-1RI and IL-1RII) that mediate the cellular responses. These receptors belong to a family of receptors based on homologous receptor structure within the intracellular signaling domain. Other family members include the Drosophila protein Toll, the recently discovered mammalian Toll-like receptors (TLR), and the IL-18 receptor. Engagement of these receptors by their diverse ligands results in activation of very similar signal transduction cascades through use of common signaling intermediates. These signal transduction cascades lead to the activation of cellular responses that are known to regulate the innate immune response. Therefore, elucidating the function and redundancy of this receptor family is essential to the understanding of the innate immune response. This review examines each member of this receptor family and emphasizes similarities and potential differences in both receptor structure and signal transduction pathways to further the understanding of this complex receptor family.
Publication Types:
Review
PMID: 11054272 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
5: Int J Mol Med. 1998 Mar;1(3):551-7.
Structure of and signal transduction through interleukin-4 and interleukin-13 receptors (review).
Murata T, Obiri NI, Puri RK.
First Department of Internal Medicine, School of Medicine, Yokohama City University, Yokohama 236, Japan.
We have recently demonstrated that two different forms of IL-4R exist; classical or alternative. The classical IL-4R is predominantly expressed in hematopoietic cells and consist of IL-4R and IL-2Rgammac (gammac) chains. On the other hand, alternative form of IL-4R is predominantly expressed in non-hematopoietic cells and consists of IL-4R and IL-13Ralpha' chains. Moreover, the alternative form of IL-4R is also utilized as a functional component IL-13R complex. It has been shown that the phosphorylation and activation of JAK3 tyrosine kinase is crucial for IL-4 activation of STAT6 in hematopoietic cells. However, we have recently demonstrated that non-hematopoietic cells lack JAK3 expression. We also demonstrated that in these cells, STAT6 activation is mediated through JAK1 and JAK2 tyrosine kinases instead. Furthermore, our results show that IL-4 and IL-13 signals are transmitted through the alternative form of IL-4R in these cells. Thus, major differences exist between hematopoietic and non-hematopoietic cells with regard to structure and signal transduction through IL-4R and IL-13R systems.
Publication Types:
Review
PMID: 9852261 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
6: Int Rev Immunol. 1998;16(3-4):345-64.
Interleukin 9 and its receptor: an overview of structure and function.
Demoulin JB, Renauld JC.
Ludwig Institute for Cancer Research and Experimental Medicine Unit, Catholic University of Louvain, Brussels, Belgium.
Interleukin-9 (IL-9) is a multifunctional cytokine produced by activated TH2 clones in vitro and during TH2-like T cell responses in vivo. Although IL-9 was initially described as a T cell growth factor, its role in T cell responses is still unclear. While freshly isolated normal T cells do not respond to IL-9, this cytokine induces the proliferation of murine T cell lymphomas in vitro, and in vivo overexpression of IL-9 results in the development of thymic lymphomas. In the human, the existence of an IL-9 mediated autocrine loop has been suggested for some malignancies such as Hodgkin's disease. Various observations indicate that IL-9 is actively involved in mast cells responses by inducing the proliferation and differentiation of these cells. Other potential biological targets for IL-9 include B lymphocytes, and hematopoietic progenitors, for which higher responses were observed with foetal or transformed cells as compared to normal adult progenitors. The IL-9 receptor is a member of the hemopoietin receptor superfamily and interacts with the gamma chain of the IL-2 receptor for signaling. Signal transduction studies have stressed the role of the Jak-STAT pathway in various IL-9 bioactivities, whereas the 4PS/IRS2 adaptor protein might also play a significant role in IL-9 signaling.
Publication Types:
Review
PMID: 9505195 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
7: Protein Sci. 1997 May;6(5):929-55.
Interleukin-6: structure-function relationships.
Simpson RJ, Hammacher A, Smith DK, Matthews JM, Ward LD.
Joint Protein Structure Laboratory, Ludwig Institute for Cancer Research, (Melbourne Tumour Biology Branch), Parkville, Victoria, Australia. simpson@licre.ludwig.edu.au
Interleukin-6 (IL-6) is a multifunctional cytokine that plays a central role in host defense due to its wide range of immune and hematopoietic activities and its potent ability to induce the acute phase response. Overexpression of IL-6 has been implicated in the pathology of a number of diseases including multiple myeloma, rheumatoid arthritis, Castleman's disease, psoriasis, and post-menopausal osteoporosis. Hence, selective antagonists of IL-6 action may offer therapeutic benefits. IL-6 is a member of the family of cytokines that includes interleukin-11, leukemia inhibitory factor, oncostatin M, cardiotrophin-1, and ciliary neurotrophic factor. Like the other members of this family, IL-6 induces growth or differentiation via a receptor-system that involves a specific receptor and the use of a shared signaling subunit, gp130. Identification of the regions of IL-6 that are involved in the interactions with the IL-6 receptor, and gp130 is an important first step in the rational manipulation of the effects of this cytokine for therapeutic benefit. In this review, we focus on the sites on IL-6 which interact with its low-affinity specific receptor, the IL-6 receptor, and the high-affinity converter gp130. A tentative model for the IL-6 hexameric receptor ligand complex is presented and discussed with respect to the mechanism of action of the other members of the IL-6 family of cytokines.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 9144766 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
8: Vitam Horm. 1997;53:27-63.
Structure and function of interleukin-1 beta converting enzyme.
Tocci MJ.
Department of Molecular Immunology, Merch Research Laboratories, Rahway, New Jersey 07065, USA.
An overwhelming body of evidence has shown that IL-1 beta is a major mediator of inflammatory disease (Tocci and Schmidt, 1996). The discovery of ICE, a unique processing enzyme involved in the production of active IL-1 beta, has provided a new approach to specifically block the production of this potent cytokine. Consequently, the discovery and development of inhibitors against the enzyme could hold great promise therapeutically. Potent inhibitors of the enzyme would be useful in the treatment of a number of important inflammatory diseases and potentially in the management of leukemia (Arend, 1993b; Estrov and Talpaz, 1996). A number of key questions must be answered before the therapeutic potential of such inhibitors can be realized. The development of a pharmaceutically acceptable cysteine proteinase inhibitor will almost certainly involve new chemical strategies gauged at safely inactivating the enzyme. For such inhibitors, it will be necessary to achieve selectivity for ICE from among the growing number of ICE family members while retaining potency. It will also be important to establish the level of inhibition of IL-1 beta required to achieve therapeutic efficacy. The studies comparing IL-1 beta- and ICE-deficient mice suggest that complete abrogation of IL-1 beta is required to achieve efficacy in models of inflammation. It is not known if this is the case in humans. Understanding the source of the residual IL-1 beta produced in ICE-deficient mice will be important in order to ascertain if a similar mechanism could generate active IL-1 beta in patients receiving if a ICE inhibitor. As for ICE itself, a number of formidable questions remain regarding its regulation and mechanism of activation. Answering these questions experimentally will present a major challenge due to the extremely low levels of enzyme present in cells. Studies on other family members may provide easier access to some of these questions and provide clues that can be applied to ICE. The components of the pathway involved in IL-1 trafficking and secretion are unknown, as are the mechanisms of ICE activation and regulation. Clearly other cellular proteins that have yet to be discovered will be involved in each of these processes, opening up new avenues of research in this field.
Publication Types:
Review
PMID: 9197177 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
9: Ann N Y Acad Sci. 1995 Jul 21;762:222-36; discussion 236-7.
Membrane-bound and soluble interleukin-6 receptor: studies on structure, regulation of expression, and signal transduction.
Heinrich PC, Graeve L, Rose-John S, Schneider-Mergener J, Dittrich E, Erren A, Gerhartz C, Hemann U, Lütticken C, Wegenka U, et al.
Institut für Biochemie, RWTH Aachen, Germany.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 7545364 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
10: Cancer Treat Res. 1995;80:143-85.
Structure and function of interleukin-4 and its receptor.
Puri RK.
Laboratory of Molecular Tumor Biology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA.
Publication Types:
Review
PMID: 8821577 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
11: Acta Haematol Pol. 1995;26(3):257-62.
[Interleukin 2 receptor (Il-2): structure and function]
[Article in Polish]
Dmoszyńska A, Roliński J.
Kliniki Hematologii AM w Lublinie.
Interleukin 2 and its receptor play a crucial role in the growth and differentiation of many cells such as lymphocytes T and B, NK cells, macrophages and monocytes. Il-2 receptor (Il-2R) is involved in Il-2 induced cellular signalling. We discuss the Il-2R structure, function of three distinct subunits and the complex pathways that link the cell surface receptor to the nuclear proto-oncogene production.
Publication Types:
English Abstract
Review
PMID: 8525770 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
12: Agents Actions Suppl. 1995;46:23-34.
Structure/function analysis of human interleukin 5 and its receptor.
Tavernier J, Cornelis S, Devos R, Guisez Y, Plaetinck G, Van der Heyden J.
Roche Research Gent, Belgium.
We have performed a detailed structure-function analysis of human interleukin 5 (hIL5) and its receptor. By testing a hIL5 mutant panel in a solid phase binding assay and a proliferation assay using hIL5 dependent cell-lines, areas on hIL5 involved in either the receptor alpha-subunit interaction or in receptor activation were identified. Epitope mapping data of a neutralizing and a non-neutralizing monoclonal antibody were in agreement with the mutant analysis. hIL5 binding areas on the IL5R alpha-subunit were identified by interspecies chimaera analysis. Finally, hIL5 mutants with reduced receptor activation potential have antagonistic properties.
Publication Types:
Review
PMID: 7610988 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
13: Res Immunol. 1993 Oct;144(8):590-6.
Characterization of the interleukin 4 receptor. Structure and signal transduction pathways.
Keegan AD, Wang LM, Paul WE, Pierce JH.
Laboratory of Immunology, NIAID NIH, Bethesda, MD 20892.
Publication Types:
Review
PMID: 8303078 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
14: Cancer Invest. 1993;11(5):609-23.
Interleukin-3: structure and function.
Lindemann A, Mertelsmann R.
Department of Medicine 1, University of Freiburg, Germany.
Publication Types:
Review
PMID: 8402229 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
15: Nippon Rinsho. 1992 Aug;50(8):1833-9.
[Function, molecular structure and gene expression of interleukin-11 (IL-11/AGIF)]
[Article in Japanese]
Kawashima I, Ohsumi J, Miyadai K, Takiguchi Y.
Interleukin-11 (IL-11) is a novel cytokine that was identified in a medium conditioned by the primate bone marrow-derived stromal cell line PU-34. It was originally identified as a growth factor for the IL-6-dependent plasmacytoma cell line T1165. Adipogenesis inhibitory factor (AGIF) was cloned from the human bone marrow-derived cell line KM-102. The AGIF cDNA sequence was revealed to be identical to that of the IL-11 cDNA. AGIF inhibits the process of adipogenesis of the bone marrow-derived preadipocyte cell line H-1/A. Other biological activities of IL-11/AGIF, megakaryocytopoiesis, stem-cell proliferation, hepatic acute phase responses and antigen-specific antibody responses are also summarized.
Publication Types:
English Abstract
Review
PMID: 1433976 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
16: Nippon Rinsho. 1992 Aug;50(8):1827-32.
[Function, molecular structure and gene expression regulation of interleukin-10 (IL-10)]
[Article in Japanese]
Nakahata T, Tsuji K.
Department of Pediatrics, Shinshu University School of Medicine.
Interleukin-10 has a variety of biological activities. Murine interleukin-10 inhibits cytokine production by Th2 cells in the presence of macrophages, enhances T cell proliferation, sustains the viability of B cells in vitro, induces class II MHC antigen expression on B cells, enhances mast cell proliferation in the presence of IL-3 and/or IL-4, and inhibits cytokine production by macrophages. Human interleukin-10 inhibits cytokine production by human T cells and reduces antigen-specific human T cell proliferation by downregulation of class II MHC antigen expression on monocytes. cDNA clones encoding murine and human interleukin-10 exhibit a strong homology to BCRFI in Epstein-Barr virus. BCRFI conserves only a part of interleukin-10 activities.
Publication Types:
English Abstract
Review
PMID: 1433975 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
17: Nippon Rinsho. 1992 Aug;50(8):1821-6.
[Function, molecular structure and gene expression regulation of interleukin 9 (IL-9)]
[Article in Japanese]
Sonoda Y.
Department of Hygiene, Kyoto Prefectural University of Medicine.
Interleukin-9 (IL-9)/P40 is a recently reported murine growth factor for helper T-cell clones. It is produced by ConA stimulated CD4+ T-cells or several T-cell lines such as TUC 2.15 derived from C57Bl/6 mouse. In the murine system, IL-9/P40 directly supported proliferation of mucosal type mast cells, and also induced erythroid burst formation, indirectly. On the other hand, human IL-9, which is a homologue to murine P40, was cloned from a cDNA library prepared with mRNA isolated from PHA-induced T-cell line (C5MJ2). Analysis of the sequence of cDNA revealed a striking similarity between murine and human IL-9/P40. Human IL-9 supported formation of a subpopulation of erythroid bursts that are responsive to IL-3. In this communication, identification, cloning of cDNA, and biological activities of murine and human IL-9/P40 are discussed.
Publication Types:
English Abstract
Research Support, Non-U.S. Gov't
Review
PMID: 1433974 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
18: Nippon Rinsho. 1992 Aug;50(8):1769-75.
[Function, molecular structure and gene expression of interleukin-1]
[Article in Japanese]
Kasahara T, Kuno K, Matsushima K.
Department of Medical Biology and Parasitology, Jichi Medical School.
Recent cloning of human and murine IL-1 receptor (IL-1R) has revealed that there are at least two type of IL-1R: type I IL-1R is detected on T cells and fibroblasts and consists of 552 AAs with a cytoplasmic domain of 213 AAs, while type II is detected on B cells and monocytic cell lines and consists of 398 AAs with a short stretch intracytoplasmic domain of 29 AAs. Extracytoplasmic portion of IL-1R has some homology with vaccinia virus B15 Ag or fibroblast protein ST-2, while cytoplasmic portion has considerable similarity with Drosophila toll gene. By transfecting murine type I IL-1R cDNA into a human Jurkat cell line, structural and functional potion required for the IL-1 signal transduction is determined. At least broad portion of cytoplasmic domain including 364-474 AAs from N-terminus are found to be essential, while PKC acceptor site (Ser-431 and Ser-509), and PKA acceptor site (Ser-528) are not essential for the IL-8 gene expression.
Publication Types:
English Abstract
Review
PMID: 1433966 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
19: Chem Immunol. 1992;51:107-34.
The interleukin-4 receptor: structure, function, and signal transduction.
Beckmann MP, Cosman D, Fanslow W, Maliszewski CR, Lyman SD.
Immunex Corporation, Seattle, Wash.
Publication Types:
Review
PMID: 1567539 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
20: Proteins. 1992 Jan;12(1):10-23.
Functional implications of interleukin-1 beta based on the three-dimensional structure.
Veerapandian B, Gilliland GL, Raag R, Svensson AL, Masui Y, Hirai Y, Poulos TL.
Center for Advanced Research in Biotechnology, University of Maryland, Rockville.
The molecular structure of interleukin-1 beta, a hormone-like cytokine with roles in several disease processes, has been determined at 2.0 A resolution and refined to a crystallographic R-factor of 0.19. The framework of this molecule consists of 12 antiparallel beta-strands exhibiting pseudo-3-fold symmetry. Six of the strands make up a beta-barrel with polar residues concentrated at either end. Analysis of the three-dimensional structure, together with results from site-directed mutagenesis and biochemical and immunological studies, suggest that the core of the beta-barrel plays an important functional role. A large patch of charged residues on one end of the barrel is proposed as the binding surface with which IL-1 interacts with its receptor.
Publication Types:
Review
PMID: 1553379 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
21: Ciba Found Symp. 1992;167:47-62; discussion 62-7.
Regulation of expression of the interleukin 6 gene: structure and function of the transcription factor NF-IL6.
Akira S, Isshiki H, Nakajima T, Kinoshita S, Nishio Y, Natsuka S, Kishimoto T.
Institute for Molecular and Cellular Biology, Osaka University, Japan.
The interleukin 6 (IL-6) promoter is rapidly and transiently activated by other cytokines, including IL-1 and tumour necrosis factor (TNF), as well as by phorbol esters and cyclic AMP agonists. Studies using promoter mutants suggested that an IL-1-responsive element mapped within the -180 to -123 region of the IL-6 promoter. A nuclear factor (NF-IL6) that recognized a unique sequence containing an inverted repeat, ACATTGCACAATCT, was identified within the region. Direct cloning of the human NF-IL6 revealed its similarity to C/EBP, a liver- and adipose tissue-specific transcription factor. C/EBP and NF-IL6 recognize the same nucleotide sequence, but exhibit distinct patterns of expression. NF-IL6 is expressed at a low level in normal tissues, but is rapidly and drastically induced by bacterial lipopolysaccharide (LPS) or inflammatory cytokines such as IL-1, TNF and IL-6. Recently, NF-IL6 has been shown to be identical to IL-6DBP, the DNA-binding protein which is responsible for IL-6-mediated induction of several acute-phase proteins. Evidence that NF-IL6 DNA-binding activity is increased after IL-6 stimulation without increased NF-IL6 protein synthesis demonstrates the importance of post-translational modification. There are some results indicating that phosphorylation is involved in transcriptional and binding activities of NF-IL6. Taken together, these findings indicate that NF-IL6 may be an important transcription factor on the signal transduction pathways of IL-1 and IL-6.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 1385054 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
22: J Invest Dermatol. 1990 Jun;94(6 Suppl):27S-32S.
Interleukin-2 and the IL-2 receptor: new insights into structure and function.
Kuziel WA, Greene WC.
Howard Hughes Medical Institute, Department of Medicine, Durham, North Carolina.
Interleukin-2 (IL-2) was originally identified in 1976 as a growth factor for T lymphocytes. Since that time it has become an important mediator of immune function through its effects on the growth, development, and activity of T and B lymphocytes, natural killer cells, and lymphokine-activated killer cells. Only cells that bear a specific receptor for IL-2 respond to its immunoregulatory effects. Of all the lymphokine-receptor systems in immunology, perhaps most is known about the structure, function, and binding properties of IL-2 and its cognate receptor. There are two distinct, membrane-associated IL-2 binding components in the high-affinity IL-2 receptor: an alpha subunit and a beta subunit, which associate in a non-covalent manner. Each of these polypeptides can occur on the cell surface in the absence of the other and bind IL-2, although with only low or intermediate affinity relative to the high-affinity receptor complex. The primary structure of each chain has now been deduced from full-length cDNA. The rapid rate of association between IL-2 and the IL-2R alpha subunit is important in the formation of high-affinity binding sites, and the inducibility of the alpha gene contributes to the highly regulated and transient display of high-affinity IL-2R. The IL-2R beta chain controls the slow dissociation rate of IL-2 from the high-affinity receptor. Also, IL-2R beta appears centrally involved in internalization of IL-2 and signal transduction, functions mediated presumably through its long intracytoplasmic domain. However, the actual mechanism of signal transduction in the IL-2/IL-2R system remains undefined. IL-2R beta is a member of a novel family of cytokine-receptor proteins that includes receptors for IL-4, IL-6, and erythropoietin.
Publication Types:
Review
PMID: 1693645 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
23: Philos Trans R Soc Lond B Biol Sci. 1990 Mar 12;327(1239):187-92.
Structure, function, and regulation of the interleukin-2 receptor and identification of a novel immune activation gene.
Leonard WJ, Gnarra JR, Napolitano M, Sharon M.
Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892.
This chapter is divided into two sections, the first dealing with a novel immune activation gene, denoted Act-2. This gene encodes a secreted protein that may represent a new cytokine. The Act-2 protein shares significant homology with proteins in two related families of small secreted proteins. Act-2 is rapidly synthesized by activated T cells, B cells and monocytes. The second section deals with interleukin-2 receptors. These receptors are now known to be comprised of three distinct classes of receptors, formed by various combinations of two IL-2 binding proteins, the alpha and beta chains. The low-affinity receptors contain alpha, but not beta chains; the intermediate-affinity receptors contain beta, but not alpha chains, and the high-affinity receptors contain both alpha and beta chains. The beta chain appears to be tyrosine phosphorylated. We discuss evidence for the existence of another protein of relative molecular mass 100,000, which appears to be a subunit of at least the high-affinity receptor.
Publication Types:
Review
PMID: 1969658 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
24: Semin Immunol. 1990 Mar;2(2):119-28.
The human interleukin-2 receptor: insights into subunit structure and growth signal transduction.
Fung MR, Greene WC.
Howard Hughes Medical Institute, Department of Medicine and Microbiology-Immunology, Duke University Medical Center, Durham, NC 27710.
Lymphokine-dependent T cell proliferation is regulated in part by the cell surface expression of high affinity interleukin-2 receptors (IL-2R). The functional, high affinity form of the IL-2 receptor is comprised of two ligand binding components, IL-2R alpha (Tac, p55) and IL-2R beta (p70/75). In the absence of the other subunit, IL-2R alpha and IL-2R beta bind ligand with only low or intermediate affinity, respectively. The inducible and transient expression of IL-2R alpha regulates the display of high affinity receptors, while IL-2R beta appears to contribute importantly to growth signal transduction. Although the primary structure of both receptor chains has now been elucidated, the mechanism of growth signal transduction through the high affinity IL-2R remains undefined. Of note, IL-2R beta belongs to a novel family of cytokine receptors including the binding proteins for IL-3, IL-4, IL-6, erythropoietin, and granulocyte-macrophage colony-stimulating factor. These various receptors may well utilize a common intracellular signalling pathway.
Publication Types:
Comparative Study
Research Support, Non-U.S. Gov't
Review
PMID: 2129904 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
25: Prog Clin Biol Res. 1990;352:179-87.
Structure and function of interleukin-2 receptors.
Leonard WJ, Sharon M, Gnarra JR.
Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892.
Publication Types:
Review
PMID: 2205861 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
26: Prog Growth Factor Res. 1990;2(4):193-205.
Interleukin-1 receptor antagonist: discovery, structure and properties.
Arend WP.
Department of Medicine, University of Colorado Health Sciences Center, Denver 80262.
Interleukin-1 receptor antagonist (IL-1ra) is a recently-described member of the IL-1 family. This unique human protein has 30% amino acid sequence homology to IL-1 beta and binds to human types I and II IL-1 receptors without apparent cellular activation. IL-1ra blocks the in vitro stimulatory effects of IL-1 on thymocytes, fibroblasts, endothelial cells and bone cells. In addition, IL-1ra is a potent inhibitor of the inflammatory effects of IL-1 in vivo. IL-1ra represents the first naturally-occurring cytokine inhibitor and may be important in modulating IL-1 effects in both normal and abnormal physiology.
Publication Types:
Review
PMID: 2151936 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
27: Ann Ist Super Sanita. 1990;26(3-4):273-82.
Human interleukin 1: structure-function relationship.
Boraschi D, Tagliabue A.
Laboratorio di Immunofarmacologia, Centro di Ricerche Sclavo, Siena, Italy.
The pleiotropic activities of IL-1 have fostered a series of studies on the structure-function relationship in these proteins. The most extensively studied in this respect has been human IL-1 beta. It has been shown that enzymatic cleavage of the precursor protein to generate the mature polypeptide appears necessary for its full biological activity. The almost complete integrity of the mature IL-1 beta protein is also required for its ability to bind to the receptor and trigger cellular functions. However, by the use of monoclonal antibodies and recombinant or synthetic peptides, it has been possible to map some IL-1 beta regions important for different activities. Both N-terminal and C-terminal fragments are important for receptor binding. A domain around amino acids 187-204 is apparently involved in the hyperalgesic effects of IL-1 beta. Finally, the fragment in position 163-171 appears to be responsible for a restricted series of the IL-1 beta activities, mainly directed to the immune system, although irrelevant for inflammation-related effects and unable of binding to the IL-1R. The understanding of the structure-function relationship of IL-1 obtained so far is expected to give rise within a short time to a new generation of synthetic and/or recombinant derivatives to be experimented for clinical purposes.
Publication Types:
Review
PMID: 2091500 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
28: Biotherapy. 1989;1(4):377-89.
Structure-function relationship of interleukin-1 giving new insights for its therapeutic potential.
Boraschi D, Tagliabue A.
Laboratory of Immunopharmacology, Sclavo Research Center, Siena, Italy.
The pleiotropic activities of IL-1 have fostered a series of studies on the structure-function relationship in these proteins. In fact, the attempt to dissociate different biological functions of IL-1 should simplify its therapeutic use. About human IL-1 beta, which has been more extensively studied in this respect, enzymatic cleavage of the precursor protein to generate the mature polypeptide appears necessary for its full biological activity. The almost complete integrity of the mature IL-1 beta protein is also required for its ability to bind to the receptor and trigger cellular functions. However, by the use of monoclonal antibodies and recombinant or synthetic peptides, it has been possible to map some IL-1 beta regions important for different activities. Both N-terminal and C-terminal fragments are important for receptor binding. A domain around amino acids 187-204 is apparently involved in the hyperalgesic effects of IL-1 beta. Finally, the fragment in position 163-171 appears to be responsible for a restricted series of the IL-1 beta activities, mainly directed to the immune system, although irrelevant for inflammation-related effects and unable of binding to the IL-1R. It is thus possible, within the sequence of a cytokine, to isolate selectively active domains. This will give us new tools for new therapeutic approaches. Thus, IL-1 might be the prototype of a new generation of cytokines developed with the goal of stimulating specific biological activities without activating the cascade effects which are typical for many cytokines.
Publication Types:
Review
PMID: 2701651 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
29: Sb Ved Pr Lek Fak Karlovy Univerzity Hradci Kralove Suppl. 1989;32(4):397-411.
[Interleukin 2. Biochemical aspects of structure and function. Review]
[Article in Czech]
Kovárová H, Stulík J, Macela A.
Ustav lékarské biochemie, II. katedry interních oborů, farmakologie a lékarské biochemie.
During the last several years, the important progress has been achieved in studying activation and proliferation processes altogether with differentiation of mononuclear cells and regulatory course of immune response. In addition to molecular biology, also the biochemical characterization of interleukins, mainly Interleukin 2 (IL 2), is of a substantial import. IL 2 is actionning as an amplificator of T and B immune cellular reactions, and it influences the production of lymphokines, i.e., gamma interferon as well as participates in antitumorous immunity. IL 2 belongs to the range of products being secreted by T lymphocytes following the specific antigenic or polyclonal mitogenic simulation of cells. It can be classed as a growth factor of cells and regulatory factor of immune responsiveness. The human IL 2 was isolated as a protein with Mr 16 kD. On the basis of complementary DNA, the molecular weight has been determined for IL 2 as 15.4 kD. The IL 2-related human gen is localized on 4th chromosome and the product of the respective gen is a protein composed of 133 amino acids. This very protein undergoes glycosylation on the 3d position having alpha-helicoid conformation. The murine IL 2 occurs rather as a dimer composed of two protein chains with Mr 16-18 kD. Variable degrees of glycosylation involve the heterogeneity and pI differences in isolated forms of IL 2. Actions of IL2 are triggered by its interaction with specific receptor, which appears on the T cells no sooner as they are activated by the antigen or mitogen. Following the IL 2 with receptor interaction, the hydrolysis of phosphatidylinositolphosphate occurs intracellularly as well as activation of proteinkinase C and a track of other biochemical reactions non-elucidated till now, which lead up to the transcription regulation of genes and transfer of mitotic apparatus from G1 into S phase of cellular cycle and of division of cells.
Publication Types:
English Abstract
Review
PMID: 2701131 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
30: Adv Exp Med Biol. 1989;254:61-5.
Structure-function relationships for high and low-affinity interleukin 2 receptors.
Robb RJ.
Medical Products Department E. I. du Pont de Nemours & Co. Glenolden, PA 19036.
Publication Types:
Review
PMID: 2683608 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
31: Year Immunol. 1989;5:46-58.
The human interleukin-2 receptor. Structure and molecular regulation.
Leonard WJ, Sharon M, Cross SL.
Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, Bethesda, Md.
Publication Types:
Review
PMID: 2652930 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
32: Year Immunol. 1989;5:126-59.
Interleukin-4: molecular structure and biochemical characteristics, biological function, and receptor expression.
Ohara J.
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, Bethesda, Md.
Publication Types:
Review
PMID: 2652925 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
33: Tanpakushitsu Kakusan Koso. 1988 Sep;33(11):1793-802.
[Interleukin-1: a multifunctional molecule in inflammation and immune response--its structure and function in defence system]
[Article in Japanese]
Goto F.
Publication Types:
Review
PMID: 2977227 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
34: Immunol Rev. 1988 Feb;102:189-212.
Structure and function of interleukin 4 and 5.
Sideras P, Noma T, Honjo T.
Department of Medical Chemistry, Kyoto University Faculty of Medicine, Japan.
Publication Types:
Review
PMID: 3284814 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
35: Ann N Y Acad Sci. 1988;546:116-21.
The human interleukin-2 receptor. Recent studies of structure and regulation.
Greene WC, Böhnlein E, Siekevitz M, Franza BR, Lowenthal J.
Howard Hughes Medical Institute, Duke University Medical Center, Durham, North Carolina 27710.
Publication Types:
Review
PMID: 3073691 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
36: Recent Prog Horm Res. 1988;44:141-55.
New insights into the structure of high-affinity interleukin-2 receptors.
Greene WC, Wano YJ, Dukovich M.
Publication Types:
Review
PMID: 3064206 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
37: Blood Rev. 1987 Dec;1(4):254-66.
Interleukin 2 and its receptor: structure, function and therapeutic potential.
Malkovský M, Sondel PM.
MRC Clinical Research Centre, Harrow, Middlesex, UK.
In this review, salient molecular, biochemical and functional features of human interleukin 2 (IL-2), its membrane receptor, and its clinical relevance are outlined. We also describe experimental systems, where observed biological or pharmacological effects of IL-2 could be applied to corresponding clinical situations. In particular, IL-2 has been intensively studied in the context of cancer therapy. We discuss the rationale for the use of IL-2 in cancer treatment and our experience in this area. A better understanding of the IL-2 system and, specifically, the nature of signals transduced through it will allow us to manipulate the immune response in a variety of different ways, resulting in new approaches to investigation of immune responsiveness in general. This may have a profound impact on clinical medicine.
Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 3332110 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
38: Clin Res. 1987 Sep;35(5):439-50.
The human interleukin-2 receptor: a molecular and biochemical analysis of structure and function.
Greene WC.
Publication Types:
Review
PMID: 2889557 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
39: Immunol Rev. 1986 Aug;92:81-101.
The murine interleukin-2 receptor: biochemical structure and regulation of expression.
Malek TR, Ashwell JD, Germain RN, Shevach EM, Miller J.
Publication Types:
Review
PMID: 3091485 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
40: Immunol Rev. 1986 Aug;92:29-48.
The human interleukin-2 receptor: analysis of structure and function.
Greene WC, Depper JM, Krönke M, Leonard WJ.
Considerable information presently exists regarding the molecular, biochemical, and biological features of the human IL-2 receptor. The IL-2 receptor protein, multiple receptor mRNAs, and a single structural gene have now been identified. The important role of this receptor in normal T-cell growth is well established and its potential participation in B-cell growth and differentiation appreciated. The availability of cloned gene products for both the IL-2 receptor and IL-2 may permit the future development of novel biological agents capable of either augmenting or blunting the T-cell immune response. The intriguing interrelationship of HTLV-I and -II infection and altered IL-2 receptor expression is now being unraveled. However, the structural difference in high and low affinity receptors as well as the mechanism by which signals for T-cell growth are propagated through the high affinity receptor remain dominant, unanswered questions in the field.
Publication Types:
Review
PMID: 3091481 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
41: Immunol Rev. 1986 Aug;92:103-20.
Structure and function of the interleukin 2 receptor: affinity conversion model.
Shimizu A, Kondo S, Sabe H, Ishida N, Honjo T.
We cloned cDNAs of the human and mouse IL-2 receptors. Comparison of their structures allowed us to identify several conserved regions localized to exons 2 and 4, the cytoplasmic portion and the transmembrane portion. These regions might be important for the functions of the IL-2 receptor. The human IL-2 receptor, which was expressed on an IL-2-dependent murine T-cell line, CTLL-2, by cDNA transfection, was shown to be functionally active by blocking the endogenous mouse IL-2 receptor with monoclonal antibodies. On the other hand, the human IL-2 receptors expressed on non-lymphoid cells were functionally inactive. They were unable to mediate the growth signal, were of low affinity species and aberrant in internalization. We postulated that the dysfunction of the IL-2 receptors in non-lymphoid cells would be due to the absence of the putative converter protein which is expressed specifically in lymphoid cells. Since the human IL-2 receptor is active in the murine T cell, the converter may interact with the receptor at the portions conserved between man and mouse. We proposed the affinity conversion model that explained the high affinity state of the receptor by the ternary complex formation between IL-2, the IL-2 receptor and the converter.
Publication Types:
Comparative Study
Research Support, Non-U.S. Gov't
Review
PMID: 3091479 [PubMed - indexed for MEDLINE]
| Navigate through the articles | |
Interleukin Expression
|
Interleukin Function
|
|
|