1: Vitam Horm. 2006;74:357-70.


Regulation of osteoclast differentiation and function by interleukin-1.

Nakamura I, Jimi E.

Department of Rheumatology, Yugawara Kosei-Nenkin Hospital, Ashigara-shimo, Kanagawa 259-0314, Japan.

Interleukin-1 (IL-1) is a multifunctional cytokine that regulates various cellular and tissue functions. Among tissues, bone is the most sensitive to IL-1. IL-1 is a potent cytokine for bone resorption and participates in the multiple steps of osteoclast recruitment, such as differentiation, multinucleation, activation, and survival. On the other hand, considerable evidence has been accumulated over the past 10 years to indicate that this cytokine plays key roles in pathological bone destruction in a variety of human diseases, including rheumatoid arthritis, osteoporosis, and periodontal disease. In this chapter, we review the history of "IL-1 in bone" and the locus of this cytokine "from laboratory bench to bedside." A better understanding of the role of IL-1 in osteoclastic bone resorption would provide opportunities for developing new therapeutics to treat diseases of the bone.

Publication Types:
Review

PMID: 17027523 [PubMed - indexed for MEDLINE]

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2: Biomaterials. 2007 Jan;28(3):371-82. Epub 2006 Sep 15.


The interrelated role of fibronectin and interleukin-1 in biomaterial-modulated macrophage function.

Schmidt DR, Kao WJ.

School of Pharmacy, University of Wisconsin-Madison, 777 Highland Ave., Madison, WI 53705, USA.

Macrophages play a critical role in mediating the host response to biomaterials, perhaps most notably by guiding the host inflammatory response through the release of inflammatory molecules such as the cytokine interleukin-1 (IL-1). The extent of the macrophage response following interaction with the biomaterial surface contributes greatly to device efficacy, yet the molecular mechanisms of this interaction are still unclear. The extracellular matrix (ECM) protein fibronectin (FN) is recognized by macrophages and frequently used in biomaterial modification to elicit greater cellular adhesion and tissue integration. Macrophage interaction with FN and other ECM molecules on the biomaterial surface has been shown to induce a variety of inflammatory responses, thus both FN and IL-1 can be utilized as model molecules to better understand the mechanisms of material-mediated macrophage responses. This literature review presents a comprehensive survey of past and current research on the interrelated role of IL-1, FN, and FN-derivatives in determining biomaterial-modulated macrophage function.

Publication Types:
Research Support, N.I.H., Extramural
Review

PMID: 16978691 [PubMed - indexed for MEDLINE]

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3: Adv Ther. 2006 Mar-Apr;23(2):208-17.


Anakinra (interleukin-1 receptor antagonist) has positive effects on function and quality of life in patients with rheumatoid arthritis.

Kavanaugh A.

Center for Innovative Therapy, Division of Rheumatology, Allergy, and Immunology, University of California, San Diego, La Jolla, California 92093-0943, USA.

Rheumatoid arthritis (RA) has severe and lasting effects on quality of life. This review (1) describes the disease progression, disability, and joint destruction that seriously alter a patient's quality of life, and (2) explains how the interleukin-1 receptor antagonist (IL-1Ra), anakinra, retards the progress of disease, thereby improving outcomes. Relevant articles were reviewed with a focus on RA, anakinra, and functional and quality-of-life outcomes. In randomized, controlled trials, the IL-1Ra anakinra provided meaningful benefits for patients with active RA, such as decreased signs and symptoms of disease, slower radiographic disease progression, reduced disability, and improved health-related quality of life. The biologic agent, anakinra, provides to patients with RA a valuable treatment option that has a positive impact on both function and quality of life.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 16751154 [PubMed - indexed for MEDLINE]

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4: Postepy Hig Med Dosw (Online). 2005 Mar 7;59:56-67.


[Function of the interleukin-1 gene system in immunomodulation, apoptosis and proliferation in the male gonad]

[Article in Polish]

Rozwadowska N, Fiszer D, Kurpisz M.

Instytut Genetyki Człowieka PAN w Poznaniu.

Spermatogenesis is a phenomenon where two main processes proliferation and apoptosis, meet. Slight changes in their activities could lead to different pathologies, such as fertility disorder (excessive apoptosis) or testicular cancer (overproliferation).The IL-1 gene family includes genes which play important roles in both these processes and consists of IL-1?, IL-1ss, IL-18, the IL-1 receptor antagonist (IL-1RA), two IL-1 receptors (IL-1RI, IL-1RII), the IL-18 receptor (IL-18R?), and the receptor-associated proteins - IL-1RAcP and IL-18Rss. Caspase-1 (ICE - interleukin-1 converting enzyme), directly connected with apoptosis and responsible for the cleavage of IL-1b and IL-18, is also a member of the IL-1 family. The system of the numerous IL-1 receptors and their signal transduction involving protein cascades provokes a range of gene expressions necessary for the initiation and maintenance of inflammatory reaction. In the testis, IL-1 is constitutively expressed, where it creates a unique microenvironment for diploid gametogenic cell conversion into specialized haploid spermatozoa. It may also be an element of the physiological protection from autoimmune attack by host testicular antigens and a part of immune privilege. This review is to summarize the knowledge of the local control of spermatogenesis and immunomodulation in the male gonad. As infertility is one of the main problems of industrialized countries, study of the pathophysiology of the male genital tract appears essential in future clinical practice.

Publication Types:
English Abstract
Review

PMID: 15761387 [PubMed - indexed for MEDLINE]

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5: Eur Cytokine Netw. 2004 Oct-Dec;15(4):279-89.


Interleukin-7 (IL-7): immune function, involvement in the pathogenesis of HIV infection and therapeutic potential.

Beq S, Delfraissy JF, Theze J.

Unité d'Immunogénétique Cellulaire, Département de Médecine Moléculaire, Institut Pasteur, 25 rue du Dr Roux, 75724 Paris Cedex 15, France.

Interleukin 7 (IL-7), which is constitutively produced particularly by stromal cells from the bone marrow and thymus, plays a crucial role in T cell homeostasis. This cytokine is implicated in thymopoiesis since it sustains thymocyte proliferation and survival. It regulates peripheral naive T cell survival by modulating the expression of the anti-apoptotic molecule Bcl-2, and sustains peripheral T cell expansion in response to antigenic stimulation. Infection by the human immunodeficiency virus (HIV) leads to severe T lymphopenia and general immune dysfunction. Increased IL-7 plasma levels are generally observed in HIV-infected patients. The existence of an inverse correlation between IL-7 plasma levels and the CD4+ T cell count suggests that a direct feedback mechanism is working to restore peripheral T cell counts in lymphopenic patients. Here, IL-7 plasma levels are a good predictive marker of CD4+ T cell restoration during therapy. Combinations of antiretroviral treatments considerably slow disease progression. They drastically decrease the viral load and, in most patients, significantly increase peripheral CD4+ T cell counts. However, despite their usual ability to reduce viral replication, such treatments often fail to reverse lymphopenia and do not restore specific antiviral immune responses. IL-7, based therapy, combined with efficient antiretroviral treatment, may be beneficial to HIV-infected patients by promoting thymic output, sustaining naive T cell counts and increasing memory T cell activation.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 15627636 [PubMed - indexed for MEDLINE]

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6: Cytokine. 2004 Nov 7;28(3):109-23.


Overview of interleukin-2 function, production and clinical applications.

Gaffen SL, Liu KD.

University at Buffalo, State University of New York, Department of Oral Biology and Department of Microbiology, 3435 Main Street, Buffalo, NY 14214, USA. sgaffen@buffalo.edu

The existence of interleukin (IL)-2 has been recognized for over 25 years, and it remains one of the most extensively studied cytokines. Here we present a broad overview of IL-2 history, functional activities, biological sources, regulation and applications to disease treatment. IL-2 exerts a wide spectrum of effects on the immune system, and it plays crucial roles in regulating both immune activation and homeostasis. Both IL-2 and its multipartite receptor are prototypical of the Type I receptor superfamily, and both have been exploited in numerous ways in the clinic. Despite the wealth of information generated about IL-2 from in vitro culture systems, in vivo mouse knockout models, and clinical trials in humans, fascinating new aspects of its functions in the immune system continue to emerge.

Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 15473953 [PubMed - indexed for MEDLINE]

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7: 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]

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8: J Autoimmun. 2003 Jun;20(4):273-5.


Role of interleukin-10 in the induction and function of natural and antigen-induced regulatory T cells.

Wraith DC.

Department of Pathology and Microbiology, School of Medical Sciences, University of Bristol, University Walk, Bristol BS8 1TD, UK. d.c.wraith@bris.ac.uk

Publication Types:
In Vitro
Research Support, Non-U.S. Gov't
Review

PMID: 12791311 [PubMed - indexed for MEDLINE]

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9: 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]

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10: Chest. 2003 Mar;123(3 Suppl):375S-6S.


Interleukin-13 induces surfactant function abnormality in the murine lung.

Zhu Z, Enhorning G, Zheng T, Chen Q, Chen NY, Homer R, Elias JA.

Departments of Internal Medicine, Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, CT 06520, USA. zhou.zhu@yale.edu

Publication Types:
Review

PMID: 12628990 [PubMed - indexed for MEDLINE]

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11: Immunobiology. 2000 Aug;202(2):151-67.


Interleukin-6 signal transduction and lymphocyte function.

Horn F, Henze C, Heidrich K.

Institute of Clinical Immunology and Transfusion Medicine, University of Leipzig, Germany. fhorn@medizin.uni-leipzig.de

Interleukin-6 (IL-6) is a pleiotropic cytokine that acts on a wide variety of cell types. It has important regulatory functions in the immune system, is a mediator of the acute-phase response, and is involved in the regulation of differentiation, proliferation, and survival of target cells. A major signal transduction pathway for IL-6 involves activation of JAK kinases and the transcription factor Stat3. In addition, a great many of other signalling pathways are induced. Stat3 has been shown to be a central player of IL-6 signalling in many systems whereas the functions of most other IL-6-activated pathways are not yet understood. In this review, we discuss the current knowledge on IL-6 functions in the immune system, IL-6 signal transduction, and its significance for lymphocyte function.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 10993289 [PubMed - indexed for MEDLINE]

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12: Curr Opin Hematol. 2000 May;7(3):174-7.


Interleukin-15 and its impact on neutrophil function.

Cassatella MA, McDonald PP.

Department of Pathology, University of Verona, Italy. MCNCSS@borgoroma.univr.it

Interleukin-15 is a recently discovered cytokine produced by several cell types (including fibroblasts, keratinocytes, endothelial cells, and macrophages) in response to endotoxin or microbial infection. In turn, interleukin-15 has been shown to act on various cells of the immune system, including T and B lymphocytes, natural killer cells, monocytes, eosinophils, and circulating neutrophils. In the latter instance, interleukin-15 was initially observed to induce cytoskeletal rearrangements, to enhance phagocytosis, to increase the synthesis of several cellular proteins, and to delay apoptosis. Recently, interleukin-15 has been found to elicit other functional responses in neutrophils, such as chemokine production. This review recapitulates advances made in the area of interleukin-15/neutrophil interactions.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 10786655 [PubMed - indexed for MEDLINE]

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13: Biochem Soc Trans. 1999 Feb;27(2):211-9.


Generation and function of the soluble interleukin-6 receptor.

Müllberg J, Vollmer P, Althoff K, März P, Rose-John S.

Medizinische Klinik, Abteilung Pathophysiologie, Johannes Gutenberg Universität Mainz, Germany.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 10093736 [PubMed - indexed for MEDLINE]

--------------------------------------------------------------------------------

14: 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]

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15: 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]

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16: Kidney Int. 1997 Feb;51(2):419-25.


Hypoxia-induced modulation of endothelial cell properties: regulation of barrier function and expression of interleukin-6.

Yan SF, Ogawa S, Stern DM, Pinsky DJ.

Department of Physiology, Columbia University, College of Physicians and Surgeons, New York, New York, USA.

The endothelial cell response to hypoxia involves a range of adaptive mechanisms that reflect an active response of the cell's biosynthetic and metabolic apparatus. Hypoxia-mediated suppression of endothelial barrier function, resulting in increased vascular leakage, is likely to contribute to pulmonary and cerebral edema associated with high altitude and is closely associated with a fall in intracellular cyclic AMP levels. Buttressing of this second messenger pathway in the endothelium using membrane permeant cyclic AMP analogs prevents increased vascular leakage due to hypoxia. Application of this principle to organ preservation has shown that supplementation with cyclic AMP analogs or inhibition of endogenous cAMP metabolism enables extension of the time a harvested organ can remain extracorporeally, after which transplantation is successful. The underlying mechanism through which cyclic AMP exerts its effects appears to be maintenance of vascular homeostasis in the graft. A distinct adaptive mechanism triggered in the endothelium by hypoxia is expression of the cytokine interleukin-6 (IL-6) by a novel mechanism involving transcription driven by the nuclear factor IL-6 (NF-IL-6) DNA binding site in the promoter. IL-6 may exert protective effects on vascular function, thereby limiting vascular injury by a different mechanism than those recruited by elevated cAMP levels. These studies provide insights into tow independent mechanisms through which endothelium responds to oxygen deprivation, and suggest possible new approaches to attentuate vascular injury associated with ischemia.

Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 9027716 [PubMed - indexed for MEDLINE]

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17: 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]

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18: Curr Opin Hematol. 1997 Jan;4(1):59-66.


Function and clinical use of interleukin-12.

Trinchieri G.

Wistar Institute of Anatomy and Biology, Philadelphia, PA 19104, USA.

Interleukin-12 is a heterodimeric cytokine produced by phagocytic cells, professional antigen-presenting cells such as dendritic cells and skin Langerhans cells, and B cells. Interleukin-12 production is induced by bacteria, intracellular pathogens, fungi, viruses, or their products in a T-cell-independent pathway or a T-cell-dependent pathway, the latter mediated through CD40 ligand-CD40 interaction. Interleukin-12 is produced rapidly after infection and acts as a proinflammatory cytokine eliciting production of interferon gamma, by T and natural killer cells, which activates phagocytic cells. The production of interleukin-12 is strictly regulated by positive and negative feedback mechanisms. If interleukin-12 and interleukin-12-induced interferon gamma are present during early T-cell expansion in response to antigen, T-helper type-1 cell generation is favored and generation of T-helper type-2 cells is inhibited. Thus interleukin-12 is also a potent immunoregulatory cytokine that promotes T-helper type-1 differentiation and is instrumental in the T-helper type-1-dependent resistance to infections by bacteria, intracellular parasites, fungi, and certain viruses. By inhibiting T-helper type-2 cell response, interleukin-12 has a suppressive effect on allergic reactions; by promoting T-helper type-1 responses it participates in the immunopathology responsible for several organ-specific autoimmune diseases. Viruses inducing a permanent or transient immunodepression, such as HIV and measles, may act, in part, by suppressing interleukin-12 production. Because of its ability to enhance resistance to several infectious diseases and to act as an adjuvant in vaccination, and because of its powerful antitumor effect in vivo, interleukin-12 is currently in clinical trials in cancer patients and HIV-infected patients, and it is being considered for therapeutic use in other diseases.

Publication Types:
Review

PMID: 9050381 [PubMed - indexed for MEDLINE]

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19: Med Hypotheses. 1997 Jan;48(1):47-54.


Promotion of interleukin-2 activity as a strategy for 'rejuvenating' geriatric immune function.

McCarty MF.

Nutrition 21, San Diego, CA 92109, USA.

The age-related decline in immune capacities is largely attributable to a decrease in the ability of activated T lymphocytes to achieve efficient clonal expansion. This in turn reflects a decrease in the expression of both interleukin-2 and its receptor. Nutritional/hormonal measures which up-regulate such expression may thus have a 'rejuvenatory' impact on geriatric immune function. Such measures may include: subtoxic selenium intakes, which increase the inducibility of interleukin-2 receptor; high-dose vitamin E and possibly chromium, which may counteract the down-regulatory effect of cAMP on interleukin-2 activity; as well as carotenoids and ascorbic acid. Restoring more youthful serum levels of the hormones DHEA and melatonin may also have a positive effect in this regard. In addition to their likely value for boosting geriatric immune defenses, these measures deserve evaluation as adjuvants to cancer immunotherapies and to drug treatments for HIV infection.

Publication Types:
Review

PMID: 9049989 [PubMed - indexed for MEDLINE]

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20: Stem Cells. 1996 Nov;14(6):605-18.


Function and signal transduction mediated by the interleukin 3 receptor system in hematopoiesis.

Hara T, Miyajima A.

Institute of Molecular and Cellular Biosciences, University of Tokyo, Japan.

Interleukin 3 (IL-3) promotes development of hematopoietic cells through activation of the IL-3 receptor (IL-3R) complex consisting of alpha and beta subunits. The alpha subunit binds IL-3 with low affinity and forms a high-affinity receptor with the common beta subunit (beta c). The beta c subunit does not bind any cytokine by itself but is involved in the formation of high-affinity functional receptors for IL-5 and GM-CSF. As the alpha subunits provide the specificity to cytokines and beta c plays a major role in signal transduction, IL-3, GM-CSF and IL-5 exhibit similar functions when they act on the same cells. Surprisingly, no apparent hematological defect other than a reduced number of eosinophils was found in knock-out mice lacking an entire function of IL-3, GM-CSF and IL-5; this indicates a remarkable functional overlap with other cytokine systems for hematopoiesis. Binding of the cytokines to the receptor induces activation of the JAK2 tyrosine kinase that associates with beta c and triggers the signaling events. The membrane proximal region of beta c is responsible for activation of JAK2 and STAT5, as well as for induction of c-myc. The signals induced by this region are required for cell-cycle progression and DNA synthesis. Activation of the Ras pathway requires the distal region of beta c and is involved in the suppression of apoptosis. Proliferation of hematopoietic cells requires signals for both DNA synthesis and anti-apoptosis. In this review, we describe the recent findings of the function and signal transduction mediated by the IL-3R system.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 8948019 [PubMed - indexed for MEDLINE]

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21: Immunol Today. 1996 Oct;17(10):476-81.


Interleukin 16 and its function as a CD4 ligand.

Center DM, Kornfeld H, Cruikshank WW.

Evans Memorial Dept of Medicine, Boston University School of Medicine, MA 02118, USA.

Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 8908813 [PubMed - indexed for MEDLINE]

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22: Curr Opin Hematol. 1996 Jan;3(1):87-93.


Role of interleukin-6 in macrophage function.

Akira S, Kishimoto T.

Institute for Molecular and Cellular Biology, Osaka University, Japan.

Interleukin-6 is a multifunctional cytokine important for host defense. Macrophages are potent producers of interleukin-6. Conversely, interleukin-6 acts on monocytes to induce their differentiation to macrophages. This paper reviews the in vivo roles of interleukin-6 and nuclear factor for interleukin-6 expression that have been revealed by gene targeting as well as recent progress in understanding the interleukin-6 gene regulation and signaling pathway in macrophages.

Publication Types:
Review

PMID: 9372056 [PubMed - indexed for MEDLINE]

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23: Neuroimmunomodulation. 1995 Jul-Aug;2(4):224-35.


Brain-periphery connections: do they play a role in mediating the effect of centrally injected interleukin-1 beta on gonadal function?

Turnbull A, Rivier C.

Clayton Foundation Laboratories for Peptide Biology, Salk Institute, La Jolla, Calif. 92037, USA.

The immune system and several endocrine axes communicate with each other through a network of molecules which collectively produce a coordinated response to immune challenges. This phenomenon, necessary for the survival of the organism, is thought to involve the release, by activated cells in the periphery, of proteins, called cytokines, which inform the brain about immune activation. The brain then organizes a series of neuroendocrine responses which participate in the regulation of the host response. With regard to the influence of cytokines on the hypothalamic-pituitary-gonadal axis, we know that the injection of these proteins lowers gonadotropin-releasing hormone release, which in turn inhibits luteinizing hormone (LH) secretion. These changes would be expected to decrease sex steroid production and, indeed, estrogens and testosterone are low in female and male rats, respectively, following acute intracerebroventricular (i.c.v.) injection of interleukin (IL)-1 beta. There is, however, another possibility that central cytokines could alter ovarian and testicular function independently of changes in gonadotropin levels. Prolonged i.c.v. infusion of the cytokine into the female rat brain produced a dramatic rise in progesterone levels. The absence of a comparable change in the progesterone release rate of males infused with IL-1 beta, and the presence of marked surges of prolactin (PRL) in the females, suggests that IL-1 beta altered ovarian function, and that the persistence of large corpora lutea induced PRL release. The possibility that the cytokine might stimulate the brain circuits that regulate PRL release, while possible, appears remote, because male rats injected with IL-1 beta showed significantly blunted PRL levels. In intact adult male rats, i.c.v. IL-1 beta administration caused the expected decrease in LH and testosterone levels, but was also accompanied by a loss of testicular responsiveness to gonadotropins. Though elevated levels of corticosteroids are known to interfere with normal gonadal steroidogenesis, blockade of IL-1-induced corticosterone release did not reverse the inhibitory influence of the cytokine. One mechanism that deserves attention is the possibility that i.c.v. injection of IL-1 beta might increase circulating cytokine levels, and indeed plasma IL-6 concentrations were significantly elevated in rats treated with IL-1 beta. This humoral mechanism may disrupt testicular function through the documented inhibitory effects of blood-borne cytokines on Leydig cell function. In addition, brain cytokines might influence a variety of peripheral events through direct (neural?) connections. This brief review discusses the hypothesis that there are brain-to-gonad connections that bypass the pituitary, and presents results that might support the possibility that central injection of IL-1 beta decreases testosterone secretion independently of blunted LH levels.

Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 8963751 [PubMed - indexed for MEDLINE]

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24: 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]

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25: 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]

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26: 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]

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27: Prog Neurobiol. 1994 Nov;44(4):397-432.


Gene expression and function of interleukin 1, interleukin 6 and tumor necrosis factor in the brain.

Schöbitz B, De Kloet ER, Holsboer F.

Max Plank Institute of Psychiatry, Department of Neuroendocrinology, Munich, Germany.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 7886232 [PubMed - indexed for MEDLINE]

--------------------------------------------------------------------------------

28: Stem Cells. 1994 Jul;12(4):386-93.


Effects of interleukin 6 on megakaryocytes and on canine platelet function.

Burstein SA.

Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City 73190.

The multifunctional cytokine interleukin 6 (IL-6) is a potent promoter of megakaryocytic maturation in vitro. In vivo, IL-6 has similar effects on the maturation of megakaryocytes, as shown by enhancing size, ploidy and platelet production. IL-6 is capable of augmenting the platelet count in both normal animals and those with reduced megakaryocyte mass; ongoing clinical trials suggest a similar thrombocytopoietic effect in man. Moreover, IL-6 alters platelet function, rendering them more sensitive to activation by thrombin and platelet activating factor. Finally, IL-6 promotes increases in plasma fibrinogen and von Willebrand factor, and a decrease in free protein S concentration. These modifications of the platelet and coagulant phases of the clotting mechanism may result in an overall prohemostatic tendency, which may prove beneficial for the amelioration of bleeding propensity following chemotherapy. However, additional investigation will be required to determine if IL-6-mediated alterations of hemostasis may lead to pathologic thrombosis.

Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 7951005 [PubMed - indexed for MEDLINE]

--------------------------------------------------------------------------------

29: Stem Cells. 1994 Mar;12(2):154-68.


Interleukin 12: a key modulator of immune function.

Wolf SF, Sieburth D, Sypek J.

Genetics Institute, Cambridge, Massachusetts 02174.

Interleukin (IL)-12 was cloned on the basis of its ability to activate natural killer (NK) cells and promote the development of cytolytic T cells. With further understanding of its activities, IL-12 has emerged as an important cytokine, affecting both immune and hematologic functions. It has been shown to be necessary for the T cell independent induction of interferon (IFN)-gamma, critical for the initial suppression of bacterial and parasitic infection; for the development of a Th1 response, critical for effective host defense against intracellular pathogens; and for the activation of differentiated T lymphocytes of both CD4+ and CD8+ phenotype. IL-12 thus functions to activate and to link the innate and acquired immune responses. The therapeutic potential of these activities is suggested by studies in tumor and microbial models. IL-12 has suppressed tumor growth in all murine models examined. Antimicrobial activity has been demonstrated in bacterial, yeast, parasitic, and viral models of infection. In many of these models, activity has been linked to production of IFN-gamma and, in the parasite model, to development of a Th1 response. In addition to the therapeutic potential associated with IL-12 activity in these disease models, the understanding of its role in immune development and interaction with other cytokines, particularly antagonists, such as IL-4 and IL-10, has clarified and extended our understanding of immune regulation and should lead to significant developments in understanding the progression of AIDS and the development of vaccine adjuvants able to direct the immune response.

Publication Types:
Review

PMID: 7911046 [PubMed - indexed for MEDLINE]

--------------------------------------------------------------------------------

30: Clin Immunol Immunopathol. 1993 Aug;68(2):175-80.


The effects of interleukin 1 on myocardial function and metabolism.

Hosenpud JD.

Oregon Cardiac Transplant Program, Oregon Health Sciences University, Portland 97201.

Publication Types:
Review

PMID: 7689429 [PubMed - indexed for MEDLINE]

--------------------------------------------------------------------------------

31: Ann N Y Acad Sci. 1993 Jun 23;685:713-39.


Modulation of macrophage function by transforming growth factor beta, interleukin-4, and interleukin-10.

Bogdan C, Nathan C.

Beatrice and Samuel A. Seaver Laboratory, Department of Medicine, Cornell University Medical College, New York, New York 10021.

The findings reviewed above leave no doubt as to the complexity of actions of TGF-beta, IL-4, and IL-10 on monocytes/macrophages. Along with MDF, whose actions were recently reviewed elsewhere, TGF-beta, IL-4, and IL-10 are the only presently known, purified cytokines that have been shown to have strong macrophage-deactivating effects. However, none of them can be categorized as purely macrophage deactivating since they also exert macrophage-activating effects. In vitro, their effects, both in terms of extent and direction (activating vs. deactivating), are strongly influenced by the stimulation conditions (e.g., triggering signal, cytokine concentration, timing of cytokine addition), the species (mouse vs. human), the source (blood vs. peritoneal, alveolar, colostral) and the state of differentiation/activation of the macrophage (e.g., resting vs. inflammatory). In addition, TGF-beta, as well as IL-4 and IL-10, up- and/or downregulates the function of several cell types other than macrophages, which further hampers our ability to predict, on the basis of in vitro experiments with macrophages, possible effects during an immune response in vivo. Despite this complexity, the highly reductive approach of in vitro studies has revealed important differences in the ability of TGF-beta, IL-4, and IL-10 to modulate the phenotype of monocytes/macrophages. The disparities have been most striking with regard to the secretory function of monocytes/macrophages (see Table 2). First, TGF-beta, IL-4, and IL-10 have a different spectrum of activity. Thus, TGF-beta, but not IL-4 or IL-10, can induce resting human monocytes to produce TNF, IL-1, and IL-6. Second, they affect monokine and RNI and ROI production to a different extent. For example, IL-10 is an approximately 25-fold more potent suppressor of LPS-induced TNF production by mouse macrophages than is TGF-beta. Third, they differ in their ability to overcome additional activating stimuli, so that in the presence of LPS, IL-4, but not TGF-beta or IL-10 suppresses IFN gamma-induced RNI release. Fourth, their macrophage-deactivating effects require different stimulation conditions. Thus, IL-4, but not TGF-beta, interferes with RNI release strongly only after preincubation of the macrophages. Finally, these agents deactivate macrophages by distinct mechanisms. For example, IL-10 causes massive downregulation of TNF mRNA, whereas TGF-beta suppresses TNF release on a translational level. It will be a challenge to define clinical applications for these potent macrophage modulators on the basis of their different spectrum of activities. For TGF-beta and IL-4 such studies have already been initiated.

Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 8363277 [PubMed - indexed for MEDLINE]

--------------------------------------------------------------------------------

32: 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]

--------------------------------------------------------------------------------

33: 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]

--------------------------------------------------------------------------------

34: 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]

--------------------------------------------------------------------------------

35: 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]

--------------------------------------------------------------------------------

36: 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]

--------------------------------------------------------------------------------

37: Endocr Rev. 1992 Aug;13(3):515-24.


Interleukin-1 and beta-cell function: more than one second messenger?

Argilés JM, López-Soriano J, Ortiz MA, Pou JM, López-Soriano FJ.

Departament de Bioquímica i Fisiologia, Universitat de Barcelona, Spain.

Cytokines, in particular IL-1, released mainly by infiltrating macrophages, can be one of the key mediators of immune-induced beta-cell destruction in IDDM. IL-1 is able to induce suppression of insulin release and biosynthesis in cultured rat pancreatic islets. In addition, the cytokine shows clear cytotoxic effects leading to beta-cell death. The proposed mechanisms of action of IL-1 after binding to the beta-cell receptors are varied. Concerning the cytotoxic effects of the cytokine, the role of oxygen free radicals, mainly derived from arachidonate metabolism (see Fig. 1) is clear, and possibly potentiated by a cytosolic Na(+)-mediated alkalinization of the beta-cell exposed to the cytokine. In fact, an increased influx of Na+ may explain some of the cytotoxicity since it results in concomitant water uptake leading to swelling of the endoplasmic reticulum. NO formation also seems to be related to the cytokine-induced cytotoxicity since inhibition of the NO synthase abolishes the effects of the cytokine (see Fig. 1). In relation to the inhibitory effects of the cytokine on the beta-cell, different studies point toward almost all known second messenger systems already described for several hormones, such as cAMP formation, increased phospholipase C activity, changes in cytosolic Ca++, and altered gene transcription (see Fig. 1). Of particular interest is the protease activation associated with IL-1 (a serine protease) that seems to be clearly connected with the effects of the cytokine upon the beta-cell. In conclusion, the different studies devoted to the problem of IL-1 signal transduction on the beta-cell seem to indicate that the action of the cytokine on the pancreatic insulin-secreting cells is not associated with an individual second messenger system but rather seems to be related to a plurifactorial transduction system.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 1425486 [PubMed - indexed for MEDLINE]

--------------------------------------------------------------------------------

38: Bioessays. 1992 Aug;14(8):527-33.


Role of the interleukin 5 receptor system in hematopoiesis: molecular basis for overlapping function of cytokines.

Tominaga A, Takaki S, Hitoshi Y, Takatsu K.

Department of Biology, Kumamoto University Medical School, Japan.

Interleukin 5 (IL-5) is a kind of peptide hormone released from T lymphocytes of mammals infected with microorganisms or parasites. It is an acidic glycoprotein with a molecular mass of 40 to 50 kDa that consists of a homodimer of polypeptides. It controls hematopoiesis so that it increases natural immunity. In the mouse, IL-5 acts on committed B cells to induce differentiation into Ig-producing cells and on common progenitors for CD5+ pre-B cells and CD5+ macrophages to support their survival. The antibodies secreted by CD5+ B cells seem to be responsible for the primary protection against the infection with microorganisms or parasites. It also supports the growth and/or differentiation of eosinophil precursor and mature eosinophils, which can be effective for the removal of parasites in combination with the antibodies against them. Murine IL-5 receptor (IL-5R) consists of two different polypeptide chains; alpha chain and beta chain. The IL-5R alpha chain is 60 kDa protein that binds IL-5 with low affinity. The IL-5R beta chain is a 130 kDa protein which does not bind IL-5 by itself but is necessary to form the high affinity IL-5R. The beta chain was identified by using one of the anti-IL-5R mAb and anti-IL-3R mAb as the IL-3R homologue. This beta chain is also used as the beta chain of GM-CSF receptor. This fact suggests that there is a common signaling mechanism among these cytokines and efficient cooperation among them. At the same time, these findings may explain the overlapping role of these cytokines in the development of granulocytes.

Publication Types:
Comparative Study
Research Support, Non-U.S. Gov't
Review

PMID: 1365906 [PubMed - indexed for MEDLINE]

--------------------------------------------------------------------------------

39: 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]

--------------------------------------------------------------------------------

40: Immunol Ser. 1992;57:549-71.


Regulation of human eosinophil production and function by interleukin-5.

Lopez AF, Shannon MF, Chia MM, Park L, Vadas MA.

Institute of Medical and Veterinary Science, Adelaide, South Australia.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 1504148 [PubMed - indexed for MEDLINE]

--------------------------------------------------------------------------------

41: 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]

--------------------------------------------------------------------------------

42: J Cell Biochem. 1991 Apr;45(4):327-34.


Expression and function of interleukin-6 in epithelial cells.

Krueger J, Ray A, Tamm I, Sehgal PB.

Rockefeller University, New York, New York 10021.

Epithelial cells both produce and are affected by interleukin-6 (IL-6). Experiments with an adenocarcinoma-derived cell line (HeLa) reveal that activation of the transfected human IL-6 promoter occurs largely through two partially overlapping second messenger (cAMP, phorbol ester)- and cytokine (IL-1, TNF, serum)-responsive enhancer elements (MRE 1, -173 to -151 and MRE II, -158 to -145). MRE I contains the typical GACGTCA cAMP and phorbol ester-responsive (CRE-TRE) motif, whereas MRE II defines a new CRE/TRE motif that contains an imperfect dyad repeat. The mechanism of dexamethasone-mediated repression of IL-6 gene expression in epithelial cells involves occlusion of the entire MRE enhancer region and of the core-promoter elements (TATA-box and RNA start site) by ligand-activated glucocorticoid receptor. Enhanced levels of IL-6 expression are observed in many solid tumors and in the hyperproliferative (and glucocorticoid-suppressible) lesions of psoriasis. In cell culture, IL-6 enhances, inhibits, or has no effect on the proliferation of epithelial cells depending upon the cell-type examined. IL-6 enhances proliferation of keratinocytes but inhibits that of breast carcinoma cell lines ZR-75-1 and T-47D. In these breast carcinoma cells, IL-6 elicits a major change in cell phenotype which is characterized by a fibroblastoid morphology, enhanced motility, increased cell-cell separation, and decreased adherens type junctions (desmosomes and focal adhesions). The new data identify IL-6 as a regulator of epithelial cell growth and of cell-cell association.

Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 2045425 [PubMed - indexed for MEDLINE]

--------------------------------------------------------------------------------

43: Ann Intern Med. 1990 Oct 15;113(8):619-27.


The soluble interleukin-2 receptor: biology, function, and clinical application.

Rubin LA, Nelson DL.

University of Toronto, Ontario.

PURPOSE: To review the biologic origin, functional characteristics, and current and potential clinical applications of a novel marker of immune system activation, the soluble interleukin-2 receptor (sIL-2R). DATA IDENTIFICATION: Studies reported since 1985 were identified by a computer search using MEDLINE as well as from bibliographies of published work. STUDY SELECTION: Sixty-two reports on the clinical applications of the sIL-2R, largely from peer-reviewed journals, were identified. These reports address the utility and significance of sIL-2R measurements in various conditions. Basic scientific investigations delineating the biochemical and molecular features of the human interleukin-2 receptor complex and the sIL-2R protein were reviewed. DATA EXTRACTION: The validity of sIL-2R quantitation as an index of in-vivo immune system activation and its usefulness as a measure of disease activity and outcome were examined. RESULTS OF DATA ANALYSIS: The quantitation of sIL-2R, a novel laboratory measure of in-vivo immune system activation, correlates reliably with disease activity in autoimmune inflammatory disorders, transplantation rejection, and specific infectious disorders. Markedly elevated serum sIL-2R levels are a particularly prominent feature of certain hematologic malignancies, such as human T lymphotropic retrovirus type I-associated adult T-cell leukemia and hairy cell leukemia, reflecting tumor burden and response to therapy. The sIL-2R level at disease onset may also reliably predict long-term prognosis in non-Hodgkin lymphoma, and it appears to provide an additional serologic measure in the assessment of clinical progression in patients with human immunodeficiency virus infection and the acquired immunodeficiency syndrome. CONCLUSIONS: Studies have suggested that sIL-2R levels offer a rapid, reliable, and noninvasive measure of disease activity, response to therapy, and, in some cases, prognosis in a broad spectrum of conditions associated with T- or B-cell immune activation.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 2205142 [PubMed - indexed for MEDLINE]

--------------------------------------------------------------------------------

44: 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]

--------------------------------------------------------------------------------

45: 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]

--------------------------------------------------------------------------------

46: 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]

--------------------------------------------------------------------------------

47: 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]

--------------------------------------------------------------------------------

48: 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]

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49: 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]

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50: 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]

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51: 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]

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52: 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]

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53: 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]

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54: 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]

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55: J Burn Care Rehabil. 1987 Nov-Dec;8(6):503-8.


Interleukin-1 and T cell function following injury.

Baker CC, Yamada AH, Faist E, Kupper TS.

Department of Surgery, Yale University School of Medicine, New Haven, Connecticut.

Sepsis is responsible for 75% of late deaths after major thermal or traumatic injury. In the clinical setting, efforts to prevent or control sepsis, or both, should include an understanding of normal host resistance, proper resuscitation techniques, and nutritional support. Previous studies have identified T suppressor cell abnormalities following thermal injury and have suggested macrophage defects after traumatic injury. Although major thermal injury is easier to quantify than mechanical trauma, both insults can stress patients' host resistance to a maximal degree, leading to profound and often fatal immunosuppression. Recent studies summarized in this paper have suggested that the macrophage and the interleukin system may play a major role in initiating some of these immune abnormalities following injury.

Publication Types:
Review

PMID: 2963826 [PubMed - indexed for MEDLINE]

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56: 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]

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57: Biochem Pharmacol. 1987 Feb 1;36(3):301-5.


Modulation of endothelial function by interleukin-1. A novel target for pharmacological intervention?

Mantovani A, Dejana E.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 3545216 [PubMed - indexed for MEDLINE]

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58: Toxicol Pathol. 1987;15(3):333-7.


Interleukin 1 and interferon-gamma: cytokines that provide reciprocal regulation of macrophage and T cell function.

Schultz RM.

Department of Immunology Research, Lilly Research Laboratories, Indianapolis, Indiana 46285.

Interactions between macrophages and T cells are symbiotic, since optimal functions of both cell types require interchange of soluble mediators. Upon activation, macrophages release interleukin-1 (alias lymphocyte activating factor, leukocytic endogenous mediator, and endogenous pyrogen), a family of molecules with multivarious biological effects, ranging from induction of fever and the acute phase response to lymphocyte activation and concomitant release of interleukin-2. Interleukin-2 induces activation and replication of several subsets of precursor lymphocytes, including cytotoxic T cells, lymphokine-activated killer (LAK) cells, and natural killer (NK) cells, and enhances their cytotoxic activity for tumor cells. Both interleukin-2 and leukotrienes enhance production of immune interferon (interferon-gamma) by activated T cells. Aside from antiviral activity, interferon-gamma produces a number of immunomodulatory effects, including macrophage activation (Ia induction, antimicrobial effector function, and activation of oxidative metabolism) and augmentation of NK function. Expression of Ia on accessory cell membranes is required for the initiation of many antigen-specific, T-dependent immune responses. Interferon-gamma also synergizes with a variety of microbial agents to augment macrophage tumoricidal function and enhance interleukin-1 secretion. The production of interferon-gamma appears to have a critical role in feeding back the cascade of interleukins in a loop of amplification. Both interleukin-1 and interferon-gamma modulate release of arachidonate metabolites in various cells. This cascade of cytokines, in collaboration with arachidonate oxygenation products, regulates immunity and sets the stage for many of the events underlying inflammation. Various anti-inflammatory drugs and immunopotentiators appear to act by modulating cytokine pathways.

Publication Types:
Review

PMID: 3120294 [PubMed - indexed for MEDLINE]

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59: 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]

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60: 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]

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61: J Am Geriatr Soc. 1985 Nov;33(11):781-7.


Role of interleukin-2 in the age-related impairment of immune function.

Thoman ML.

Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 2932499 [PubMed - indexed for MEDLINE]