1: Eur J Cancer. 2006 Apr;42(6):751-9. Epub 2006 Mar 10.


Effects of micro-environment- and malignant cell-derived interleukin-1 in carcinogenesis, tumour invasiveness and tumour-host interactions.

Apte RN, Krelin Y, Song X, Dotan S, Recih E, Elkabets M, Carmi Y, Dvorkin T, White RM, Gayvoronsky L, Segal S, Voronov E.

Department of Microbiology and Immunology and Faculty of Health Sciences and The Cancer Research Center, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel. rapte@bgumail.bgu.ac.il

Interleukin-1 (IL-1) comprises a family of closely related genes; the two major agonistic proteins, IL-1alpha and IL-1beta, are pleiotropic and affect mainly inflammation, immunity and haemopoiesis. IL-1beta is active solely in its secreted form, whereas IL-1alpha is active mainly as an intracellular precursor. IL-1 is abundant at tumour sites, where it may affect the process of carcinogenesis, tumour growth and invasiveness and the patterns of tumour-host interactions. Here, we review the effects of micro-environment- and tumour cell-derived IL-1 on malignant processes in experimental tumour models. We propose that membrane-associated IL-1alpha expressed on malignant cells stimulates anti-tumour immunity, while secretable IL-1beta derived from the micro-environment or the malignant cells, activates inflammation that promotes invasiveness and induces tumour-mediated suppression. Inhibition of the function of IL-1 by the inhibitor of IL-1, interleukin-1 receptor antagonist (IL-1Ra), reduces tumour invasiveness and alleviates tumour-mediated suppression, pointing to its feasible use in cancer therapy. Differential manipulation of IL-1alpha and IL-1beta in malignant cells or in the tumour's micro-environment may open new possibilities for using IL-1 in cancer immunotherapy.

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

PMID: 16530403 [PubMed - indexed for MEDLINE]

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2: Mol Neurobiol. 2005 Oct;32(2):133-44.


Interactions of interleukin-1 with neurotrophic factors in the central nervous system: beneficial or detrimental?

Friedman WJ.

Department of Biological Sciences, Rutgers University, Newark, NJ, USA. wilmaf@andromeda.rutgers.edu

Interleukin (IL)-1 is a multifunctional cytokine that plays a key role in mediating inflammation in the brain. Many different cell types in the brain express the IL-1 receptor and respond to this cytokine by activating cell-type-specific signaling pathways leading to distinct functional responses, which collectively comprise the inflammatory response in the brain. One key effect of IL-1 in the brain is the induction of trophic factor production by glial cells, which has traditionally been considered a neuroprotective response to injury or disease. However, recent studies have shown that nerve growth factor, which is regulated by IL-1, can induce neuronal survival or apoptosis via different receptors. This article examines the interaction of IL-1 with different trophic factors in the brain.

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

PMID: 16215278 [PubMed - indexed for MEDLINE]

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3: Semin Cancer Biol. 2002 Aug;12(4):277-90.


Interleukin-1--a major pleiotropic cytokine in tumor-host interactions.

Apte RN, Voronov E.

Department of Microbiology and Immunology, Faculty of Health Sciences and The Cancer Research Center, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel. rapte@bgumail.bgu.ac.il

Interleukin-1 (IL-1) represents a family of two agonistic proteins, IL-1alpha and IL-1beta, that are pleiotropic and affect hemopoiesis, inflammation, and immunity. In the context of the producing cell, IL-1beta is solely active in its secreted form, whereas IL-1alpha is active as an intracellular precursor, as a membrane-associated cytokine and to a lesser extent as a secreted molecule. IL-1 is abundant at tumor sites, where it may not only affect the growth and invasiveness of malignant cells, but where it may also induce antitumor immunity. Here we review the effects of microenvironmental and tumor cell-associated IL-1 on malignant processes, in experimental tumor models and in cancer patients.

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

PMID: 12147202 [PubMed - indexed for MEDLINE]

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4: Vet Immunol Immunopathol. 2002 Sep 10;87(3-4):467-79.


Neuroendocrine-immune interactions in fish: a role for interleukin-1.

Engelsma MY, Huising MO, van Muiswinkel WB, Flik G, Kwang J, Savelkoul HF, Verburg-van Kemenade BM.

Cell Biology and Immunology Group, Wageningen Institute of Animal Sciences, Wageningen University, P.O. Box 338, 6700 AH Wageningen, The Netherlands.

Bi-directional communication between the hypothalamus-pituitary-adrenal (HPA)-axis and the sympathetic nervous system with the immune system is crucial to ensure homeostasis. Shared use of ligands and especially receptors forms a key component of this bi-directional interaction. Glucocorticoids (GC), the major end products of the HPA-axis differentially modulate immune function. Cytokines, especially interleukin-1 (IL-1), tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), ensure immune signalling to the neuroendocrine system. In addition, hormones from leukocyte origin such as corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH) and beta-endorphin, as well as centrally synthesised and secreted cytokines, contribute to the communication network.In teleost fish cortisol is the major product of the hypothalamus-pituitary-interrenal (HPI)-axis which is the teleost equivalent of the HPA-axis. Moderate and substantial increases in cortisol during stressful circumstances negatively affect B-lymphocytes, whereas rescue of neutrophilic granulocytes may support innate immunity. Recent elucidation of lower vertebrate cytokine sequences has facilitated research into neuroendocrine-immune interactions in teleosts and the first evidence for a significant function of interleukin-1 in the bi-directional communication is discussed.

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

PMID: 12072274 [PubMed - indexed for MEDLINE]

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5: Eur Cytokine Netw. 2001 Mar;12(1):15-21.


The interleukin-6 cytokine system in embryonic development, embryo-maternal interactions and cardiogenesis.

Seiler P, Plenz G, Deng MC.

Department of Cardiothoracic Surgery, University Münster, Albert-Schweitzer-Str. 33, D-48129 Münster, Germany.

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

PMID: 11282541 [PubMed - indexed for MEDLINE]

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6: Immunol Rev. 2000 Jun;175:47-58.


The role of the preBCR, the interleukin-7 receptor, and homotypic interactions during B-cell development.

Stoddart A, Fleming HE, Paige CJ.

Department of Immunology, University of Toronto, Ontario Cancer Institute, University Health Network, Canada. stoddart@oci.utoronto.ca

Considerable progress has been made in defining intermediate stages in the process leading from stem cells to mature B cells. Cell-bound and secreted molecules direct the progression through these stages and regulate the selection of clones from which the immune repertoire emerges. In fact, a myriad of signals derived from B-cell progenitors themselves and the microenvironment in which they develop direct the differentiation process. These signals are provided by B-cell antigen receptors (BCR) and their surrogates, and by adhesion and cytokine receptors. The co-operation of these receptors to control survival, expansion, and differentiation of early B-cell progenitors is the topic of this review. Specifically, we will summarize recent findings from our laboratory demonstrating that preBCR expression lowers the threshold for interleukin (IL)-7 responsiveness. How signals initiated by these receptors may intersect at this critical point of B-cell selection will be discussed. At the stage following IL-7 responsiveness we have shown that interactions between B-cell progenitors themselves promote their differentiation to immunoglobulin-secreting B cells. We propose that one function of stromal cells, known to be central to B lymphopoiesis, is to promote critical preB-preB homotypic interactions and ensuing signals.

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

PMID: 10933590 [PubMed - indexed for MEDLINE]

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7: Exp Clin Endocrinol Diabetes. 2000;108(2):67-71.


Thyrocyte-interleukin-1 interactions.

Rasmussen AK, Bendtzen K, Feldt-Rasmussen U.

Medical Department of Endocrinology & Institute of Inflammatory Research, Rigshospitalet, Copenhagen University Hospital, Denmark.

Autoimmune thyroid disease is the most common organ-specific autoimmune disease and is a very common cause of thyroid dysfunction such as autoimmune hypothyroidism, Graves' disease and postpartum thyroiditis. The thyroid gland from patients with autoimmune thyroid disease is morphologically characterized by massive infiltration of lymphoid cells. The interleukin-1 (IL-1) family of molecules is together with other cytokines an integral component of the complex intercellular communication required to mount and control an immune response. IL-1alpha/beta in moderate and high concentrations reversibly inhibit thyroid cell function, while IL-1beta in low concentrations stimulates thyroid cell function. The biphasic, non-cytotoxic and reversible influence of IL-1 supports a role of IL-1 in the physiological regulation of thyroid cell function. IL-1 stimulates the guanylate mediated pathways and inhibits the adenylate cyclase mediated pathways. All IL-1 effects are counteracted by IL-1 receptor antagonist indicating that the effects are exerted through activation of specific IL-1 receptors on thyrocytes. Furthermore, IL-1 induces or enhances expression of a number of immunologically active molecules such as adhesion molecules, cytokines, and complement regulatory proteins in thyroid epithelial cells. IL-1 may thus play a role during physiological as well as pathophysiological conditions contributing to for example the euthyroid sick syndrome and development of thyroid autoimmunity. This review summarizes current literature on the phenomenological in vitro influence of IL-1 on the thyroid cell.

Publication Types:
Review

PMID: 10826510 [PubMed - indexed for MEDLINE]

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8: Results Probl Cell Differ. 2000;28:53-68.


The Sertoli cell-germ cell interactions and the seminiferous tubule interleukin-1 and interleukin-6 system.

Jégou B, Stéphan JP, Cudicini C, Gomez E, Bauché F, Piquet-Pellorce C, Touzalin AM.

GERM-INSERM U435, Université de Rennes I, Bretagne, France.

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

PMID: 10626294 [PubMed - indexed for MEDLINE]

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9: Cytokine Growth Factor Rev. 1998 Sep-Dec;9(3-4):221-37.


The interleukin 1 receptor: ligand interactions and signal transduction.

Auron PE.

Department of Pathology, Harvard Medical School, Harvard Institutes of Medicine, Boston, MA 02115, USA. auron@cbrsgi.med.harvard.edu

The interleukin 1 (IL-1) receptor is a critical component in mediating the inflammatory responses of IL-1, which affect nearly every cell type. Recently, major inroads have been made toward understanding the mechanism by which IL-1 interacts with its receptor and activates signal transduction. The receptor-ligand association has been visualized by X-ray crystal structure analysis, revealing intimate details that distinguish IL-1beta from the naturally-occuring receptor antagonist. Signaling studies have focused primarily on the ability of IL-1 to transduce the activation of the transcription factor, NF-kappaB, which is of central importance to inflammatory and immune responses. Virtually all of the effort has targeted the activation of a kinase which results in the phosphorylation of the inhibitory IkappaB molecule at two serines that precedes the proteolytic degradation of this inhibitor and the release of active NF-kappaB. The recent characterization of an IL-1 receptor associated kinase (IRAK) and a continuous molecular path between this kinase and that which directly phosphorylates IkappaB would seem to all but close the basic understanding of IL-1 receptor signal transduction. However, at least half of the IL-1-dependent NF-kappaB activation is independent of IRAK and uses a novel pathway involving the recruitment of phosphatidylinositol 3-kinase (PI3K) to a distinct site within the cytoplasmic domain of the IL-1 receptor. This novel pathway for NF-kappaB activation and the fact that other important transcription factors are also activated by an IL-1 receptor-dependent signal event, clearly defines additional mechanisms that influence inflammation.

Publication Types:
Review

PMID: 9918122 [PubMed - indexed for MEDLINE]

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10: Biochem Pharmacol. 1998 Jul 15;56(2):153-6.


The HIV envelope protein gp120 in the nervous system: interactions with nitric oxide, interleukin-1beta and nerve growth factor signalling, with pathological implications in vivo and in vitro.

Corasaniti MT, Bagetta G, Rotiroti D, Nisticò G.

Faculty of Pharmacy and IBAF-CNR, Catanzaro, Italy.

The neuronal loss often described at post-mortem in the brain neocortex of patients suffering from AIDS has been proposed to be responsible for the development of the AIDS dementia complex. Neuroinvasive strains of the HIV virus infect macrophages, microglial cells, and multinucleated giant cells, but not neurones. Processing of the virus by cells of the myelomonocytic lineage yields viral products known to initiate a complex network of events that may lead to the death of neurones and to the development of AIDS-associated neurological syndrome. The HIV-1 coat protein gp120, in particular, has been proposed as a likely etiologic agent of the described neuronal loss because it causes the death of neurones in culture. More recently, it has been shown that brain cortical cell death caused in rats by intracerebroventricular injection of gp120 occurs via apoptosis. This observation broadens our knowledge of the pathophysiology of the reported neuronal cell loss and opens a new avenue of experimental research for the development of novel therapeutic strategies for the treatment of patients suffering from AIDS-associated neurological syndrome.

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

PMID: 9698067 [PubMed - indexed for MEDLINE]

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11: Mol Psychiatry. 1997 Mar;2(2):111-2.


Neuropathogenesis of HIV-1 infection: interactions between interleukin-1 and transforming growth factor-beta 1.

Vitković L.

Division of Neuroscience and Behavioral Science, National Institute of Mental Health, National Institutes of Health, Rockville, MD 20857, USA. vitkovic@helix.nih.gov

Cytokines are widely considered to function as major mediators of neuropathogenesis of HIV-1 infection. This view is based on a large amount of data obtained in vitro, in animal models and in human brain tissue obtained postmortem. Evidence for the involvement of interleukin-1 and transforming growth factor-beta 1, summarized here, indicates that these cytokines likely control HIV-1 expression in the brain and astrocytosis, the two hallmarks of brain in AIDS patients. Although the data do not reveal the precise time course of molecular and cellular changes in vivo, they strongly suggest a complex pattern of interactions whose ordering in time determines when and where HIV-1 is expressed in the brain. Further kinetic data are therefore urgently needed to shed light on the heterogeneity of HIV-1 expression in the brain.

Publication Types:
Review

PMID: 9106229 [PubMed - indexed for MEDLINE]

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12: J Mol Recognit. 1996 Sep-Dec;9(5-6):347-55.


Interleukin 5 interactions with soluble and cell surface forms of its receptor.

Li J, Cook R, Chaiken I.

Department of Molecular Immunology, SmithKline Beecham, King of Prussia PA 19406, USA.

Publication Types:
Review

PMID: 9174908 [PubMed - indexed for MEDLINE]

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13: Leuk Lymphoma. 1996 May;21(5-6):379-90.


Erratum in:
Leuk Lymphoma 2001 Nov-Dec;42(6):following 1447.

Interactions involving cyclosporine A, interleukin-6, and Epstein-Barr virus lead to the promotion of B-cell lymphoproliferative disease.

Tanner JE, Alfieri C.

Laboratory of Virology, Children's Hospital of Eastern Ontario, nd Ottawa, Canada.

Post-transplant patients undergoing prolonged Cyclosporine A (CsA) immunosuppressive therapy were reported to have an increased incidence of Epstein-Barr virus (EBV)-associated lymphoproliferative disorders. EBV-infected B cells cultured with CsA demonstrated increased EBV B-cell out-growth as compared to those cultured without CsA. Peripheral blood mononuclear cells (PBMC), following infection with EBV and CsA treatment, demonstrated increased IL-6 activity in the culture supernatant. The induction of IL-6 appeared to differ within the various lymphocyte populations. In monocytes and B cells, IL-6 expression was preferentially induced by EBV, and initiated by the binding of the two major virion glycoproteins, gp350 and gp220, to CD21, or a CD21-like receptor. Expression of IL-6 in T cells appeared to be due mainly to CsA. B cells also expressed IL-6 following EBV exposure, but not following CsA treatment. EBY-immortalized B-cell lines cultured with CsA exhibited both an increased number of cells expressing viral lytic-cycle antigens and increased amounts of lytic-cycle proteins. IL-6, which was induced by CsA in PBMC, was also capable of inducing the lytic viral cycle in several EBV-immortalized cells. When IL-6 was expressed, it was shown to act as an autocrine growth factor for B cells and to inhibit the immune system allowing for the promotion of B-cell tumors by impairing lymphokine-activated killer cells. Thus CsA treatment, in promoting both increased numbers of lytic EBV B cells and expression of the EBV paracrine growth factor, IL-6, within the microenvironment of EBV B:T cell and EBV B:monocyte interactions, may lead to increased EBV B-cell immortalization and ultimately result in the promotion of B-cell lymphomas in immunosuppressed patients.

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

PMID: 9172802 [PubMed - indexed for MEDLINE]

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14: HNO. 1991 Sep;39(9):323-31.


[Interactions and biological mechanisms of action of molecular signal peptides. II. Interleukin 2 (IL-2)]

[Article in German]

Wustrow TP.

Klinik und Poliklinik für Hals-Nasen-Ohrenkranke, Ludwig-Maximilians-Universität, München.

Interleukin 2 (IL-2) is predominantly produced by T-helper cells (TH1) having the phenotype CD4+, and by subpopulations of thymocytes after antigenic or mitogenic stimulation. IL-2 causes an indefinite growth of T-cells, and its function depends on binding to IL-2 receptors (IL-2R alpha and IL-2R beta). Thus the immune response of T cells is controlled through the expression of the IL-2 receptors and the IL-2 binding. IL-2 receptors are expressed not only by T-cells but also by B-cells, NK cells, monocytes, thymocytes, thymic stroma cells, oligodendrocytes and endothelial cells. This explains the various functions of IL-2, such as increased immunoglobulin production, growth of certain B-cell subpopulations, macrophage-dependent cytotoxicity, growth and differentiation of oligodendrocytes and proliferation of lymphokine activated killer (LAK) cells. Abnormal production of IL-2 may lead to autoimmune diseases, immunodeficiencies and, under certain circumstances, to T-cell leukemia. With antibodies against the IL-2 receptors the binding of IL-2 may be blocked to avoid auto-aggressive destruction in autoimmune diseases. LAK cells increase the growth of NK cells and T-cell cytotoxicity against transformed cells. LAK cells, especially those from tumor infiltrating lymphocytes, in conjunction with IL-2 have already been used with promising initial results in the treatment of distant metastases. In the future LAK cell therapy with IL-2 may be adopted to prevent metastases and second primary tumors in high-risk patients with head and neck cancer.

Publication Types:
English Abstract
Review

PMID: 1836210 [PubMed - indexed for MEDLINE]

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15: HNO. 1991 Aug;39(8):281-93.


[Interactions and biological mechanisms of action of molecular signal peptides. I. Interleukin 1 (IL-1)]

[Article in German]

Wustrow TP.

Klinik und Poliklinik für Hals-Nasen-Ohrenkranke Ludwig-Maximilians-Universität, Klinikum Grosshadern.

Interleukin 1 (IL-1) has several fundamental immunoregulatory, haematological, metabolic and physiological effects. It coordinates the different cellular interactions in wound healing and inflammation, but most importantly it stimulates the activation and differentiation of pre-B-cells and T-cells, the attraction of neutrophils, the recruitment of bone marrow stem cells, the stimulation of the metabolism of arachnoid acid, the degradation of proteoglycans, an increase of body temperature and loss of appetite. An altered production of IL-1 or of IL-1 inhibitors may cause profound disturbances, as in AIDS, other viral and malignant diseases and in uncontrolled inflammatory processes. Since a variety of feedback mechanisms for the stimulation or inhibition of IL-1 production have been detected, a major research goal will be to analyse and correct as curly as possible any abnormalities of inflammation or wound healing. Completely new treatment methods might become available in the future through approaches interfering with the signal transduction or processing of IL-1, especially by IL-1 receptor antagonists (IL-1RA).

Publication Types:
English Abstract
Review

PMID: 1834620 [PubMed - indexed for MEDLINE]

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16: Am J Pathol. 1987 Oct;129(1):25-33.


Warner-Lambert/Parke-Davis award lecture. Cellular interactions in the immune response. The roles of B lymphocytes and interleukin-4.

Abbas AK.

Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115.

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

PMID: 2959156 [PubMed - indexed for MEDLINE]

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17: Immunol Rev. 1980;51:215-55.


T-T cell interactions during cytotoxic T lymphocyte (CTL) responses: T cell derived helper factor (Interleukin 2) as a probe to analyze CTL responsiveness and thymic maturation of CTL progenitors.

Wagner H, Hardt C, Heeg K, Pfizenmaier K, Solbach W, Bartlett R, Stockinger H, Röllinghoff M.

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

PMID: 7000672 [PubMed - indexed for MEDLINE]