Elsevier

Biochemical Pharmacology

Volume 55, Issue 8, 15 April 1998, Pages 1139-1149
Biochemical Pharmacology

Commentaries
Cytokines and Their Roles in Pancreatic Islet β-Cell Destruction and Insulin-Dependent Diabetes Mellitus

https://doi.org/10.1016/S0006-2952(97)00492-9Get rights and content

Abstract

Insulin-dependent diabetes mellitus (IDDM) is a disease that results from autoimmune destruction of the insulin-producing β-cells in the pancreatic islets of Langerhans. The autoimmune response against islet β-cells is believed to result from a disorder of immunoregulation. According to this concept, a T helper 1 (Th1) subset of T cells and their cytokine products, i.e. Type 1 cytokines—interleukin 2 (IL-2), interferon gamma (IFNγ), and tumor necrosis factor beta (TNFβ), dominate over an immunoregulatory (suppressor) Th2 subset of T cells and their cytokine products, i.e. Type 2 cytokines—IL-4 and IL-10. This allows Type 1 cytokines to initiate a cascade of immune/inflammatory processes in the islet (insulitis), culminating in β-cell destruction. Type 1 cytokines activate (1) cytotoxic T cells that interact specifically with β-cells and destroy them, and (2) macrophages to produce proinflammatory cytokines (IL-1 and TNFα), and oxygen and nitrogen free radicals that are highly toxic to islet β-cells. Furthermore, the cytokines IL-1, TNFα, and IFNγ are cytotoxic to β-cells, in large part by inducing the formation of oxygen free radicals, nitric oxide, and peroxynitrite in the β-cells themselves. Therefore, it would appear that prevention of islet β-cell destruction and IDDM should be aimed at stimulating the production and/or action of Type 2 cytokines, inhibiting the production and/or action of Type 1 cytokines, and inhibiting the production and/or action of oxygen and nitrogen free radicals in the pancreatic islets.

Section snippets

IDDM,

1 The Result of Disordered Regulation of Immune Responses

IDDM is a disease that results from destruction of the insulin-producing β-cells in the pancreatic islets of Langerhans. Current evidence favors the concept that β-cells are destroyed by an autoimmune response directed against certain β-cell constituents (autoantigens) [1]. This autoimmune response is thought to occur in genetically predisposed persons who possess certain “susceptibility” alleles and who lack other “protective” alleles of

Cytokine Regulation of Immune Responses

Th1 and Th2 cells are characterized by their distinct cytokine secretory products [4]. Th1 cells secrete IL-2, IFNγ, and TNFβ, whereas Th2 cells secrete IL-4 and IL-10. Also, other cytokines are produced by both Th1 and Th2 cells, and Th cell phenotypes other than Th1 and Th2 exist and have other patterns of cytokine secretion. The functional significance of Th1 and Th2 cell subsets is that their distinct patterns of cytokine secretion lead to strikingly different T cell actions 4, 5, 6. Th1

Cytokine Studies in Isolated Islets

It is now well documented that cytokines can be cytotoxic to pancreatic islets in vitro7, 8. IL-1, TNFα, TNFβ, and IFNγ (in pico- to nanomolar concentrations) are cytostatic to β-cells: that is, the individual cytokines inhibit insulin synthesis and secretion, but these largely recover after the cytokine is removed. In addition, the cytokines may be cytocidal: i.e. IL-1, TNFα, TNFβ, and IFNγ, usually when added in combination, destroy the β-cells in both rodent and human islets. Because the

TH1 Cells and Cytokines as Mediators of β-Cell Destruction in IDDM

Abundant evidence now suggests that autoreactive T cells are present in the normal immune system but are prevented from expressing their autoreactive potential by other regulatory (suppressor) T cells [47]. The opposing actions of autoreactive and regulatory T cells are regulated by their respective cytokine products 4, 5, 6; one study has provided direct evidence for the operation of such a cytokine immunoregulatory balance in the avoidance of autoimmune diabetes [48]. Diabetes was induced in

Molecular Mechanisms of Cytokine Actions in Islet β-Cells

The actions of IL-1β (as a single agent) on β-cells have been studied the most, but the actions of TNFα and IFNγ (usually in combination with IL-1β) have also been examined, and a variety of mechanisms have been proposed to mediate the cytostatic and/or the cytotoxic effects of these cytokines (IL-1β, TNFα, and IFNγ) on islet β-cells. Most current evidence points to oxygen and/or nitrogen free radicals as mediators of cytokine-induced islet β-cell destruction 7, 8, 65 (Fig. 3).

Therapeutic Perspectives

Present and future approaches to prevention of human IDDM are based on recent findings regarding the roles of cytokines in the autoimmune pathogenesis of β-cell destruction. Thus, current evidence suggests that IDDM results from an immunoregulatory imbalance in which Th1 cells and their cytokine products, IFNγ, IL-2, and TNFβ (Type 1 cytokines), dominate over immunoregulatory (suppressor) Th2 cells and their cytokine products, IL-4 and IL-10 (Type 2 cytokines). Therefore, the current notion is

References (116)

  • K.-D Kroncke et al.

    Activated macrophages kill pancreatic syngeneic islet cells via arginine-dependent nitric oxide generation

    Biochem Biophys Res Commun

    (1991)
  • S. Lenzen et al.

    Low antioxidant enzyme gene expression in pancreatic islets compared with various other mouse tissues

    Free Radic Biol Med

    (1996)
  • F. Pisanti et al.

    Superoxide dismutase activity in the BB ratA dynamic time–course study

    Life Sci

    (1988)
  • G. Papaccio et al.

    Superoxide dismutase in the nonobese diabetic (NOD) mouseA dynamic time–course study

    Life Sci

    (1995)
  • A. Rabinovitch et al.

    Combination therapy with an antioxidant and a corticosteroid prevents autoimmune diabetes in NOD mice

    Life Sci

    (1992)
  • P. Hammonds et al.

    Insulin-secreting β-cells possess specific receptors for interleukin-1β

    FEBS Lett

    (1990)
  • S.L Marklund

    Regulation by cytokines of extracellular superoxide dismutase and other superoxide dismutase isoenzymes in fibroblasts

    J Biol Chem

    (1992)
  • C. Southern et al.

    Inhibition of insulin secretion by interleukin-1β and tumour necrosis factor-α via an l-arginine-dependent nitric oxide generating mechanism

    FEBS Lett

    (1990)
  • J.A Corbett et al.

    Interleukin-1β-induced formation of EPR-detectable iron-nitrosyl complexes in islets of Langerhans

    J Biol Chem

    (1991)
  • H. Kaur et al.

    Evidence for nitric oxide-mediated oxidative damage in chronic inflammation. Nitrotyrosine in serum and synovial fluid from rheumatoid patients

    FEBS Lett

    (1994)
  • J.F. Bach

    Insulin-dependent diabetes mellitus as an autoimmune disease

    Endocr Rev

    (1994)
  • B. Singh et al.

    Influence of microbial agents on the development and prevention of autoimmune diabetes

    Autoimmunity

    (1993)
  • A. Rabinovitch

    Immunoregulatory and cytokine imbalances in the pathogenesis of IDDM. Therapeutic intervention by immunostimulation?

    Diabetes

    (1994)
  • T.R. Mosmann et al.

    TH1 and TH2 cellsDifferent patterns of lymphokine secretion lead to different functional properties

    Annu Rev Immunol

    (1989)
  • S. Romagnani

    TH1 and TH2 subsetsRegulation of differentiation and role in protection and immunopathology

    Int Arch Allergy Immunol

    (1992)
  • T. Mandrup-Poulsen et al.

    Cytokines and free radicals as effector molecules in the destruction of pancreatic beta cells

    Curr Top Microbiol Immunol

    (1990)
  • A. Rabinovitch

    Roles of cytokines in IDDM pathogenesis and islet β-cell destruction

    Diabetes Rev

    (1993)
  • D. Pipeleers et al.

    Pancreatic β cells possess defense mechanisms against cell-specific toxicity

    Proc Natl Acad Sci USA

    (1986)
  • Z. Ling

    In’t Veld PA and Pipeleers DG, Interaction of interleukin-1 with islet β-cells. Distinction between indirect, aspecific cytotoxicity and direct, specific functional suppression

    Diabetes

    (1993)
  • R. Sutton et al.

    The specificity of rejection and the absence of susceptibility of pancreatic islet β-cells to nonspecific immune destruction in mixed strain islets grafted beneath the renal capsule in the rat

    J Exp Med

    (1989)
  • O. Korsgren et al.

    Characterization of mixed syngeneic-allogeneic and syngeneic-xenogeneic islet-graft rejections in miceEvidence of functional impairment of the remaining syngeneic islets in xenograft rejections

    J Clin Invest

    (1994)
  • A. Rabinovitch et al.

    IFN-γ gene expression in pancreatic islet-infiltrating mononuclear cells correlates with autoimmune diabetes in nonobese diabetic mice

    J Immunol

    (1994)
  • A. Muir et al.

    Insulin immunization of nonobese diabetic mice induces a protective insulitis characterized by diminished intraislet interferon-γ transcription

    J Clin Invest

    (1995)
  • N. Sarvetnick et al.

    Loss of pancreatic islet tolerance induced by β-cell expression of interferon-γ

    Nature

    (1990)
  • I.L Campbell et al.

    Essential role for interferon-γ and interleukin-6 in autoimmune insulin-dependent diabetes in NOD/Wehi mice

    J Clin Invest

    (1991)
  • A.K Foulis et al.

    Insulitis in type I (insulin-dependent) diabetes mellitus in manMacrophages, lymphocytes, and interferon-γ containing cells

    J Pathol

    (1991)
  • X. Huang et al.

    Interferon expression in the pancreases of patients with type I diabetes

    Diabetes

    (1995)
  • T.A Stewart et al.

    Induction of type 1 diabetes by interferon-α in transgenic mice

    Science

    (1993)
  • J. Allison et al.

    Consequences of in situ production of IL-2 for islet cell death

    Int Immunol

    (1994)
  • L. Wogensen et al.

    Production of interleukin 10 by islet cells accelerates immune-mediated destruction of β cells in nonobese diabetic mice

    J Exp Med

    (1994)
  • P.S. Ohashi et al.

    Induction of diabetes is influenced by the infectious virus and local expression of MHC class 1 and tumor necrosis factor-α

    J Immunol

    (1993)
  • S. Guerder et al.

    Costimulator B7-1 confers antigen-presenting-cell function to parenchymal tissue and in conjunction with tumor necrosis factor α leads to autoimmunity in transgenic mice

    Proc Natl Acad Sci USA

    (1994)
  • D.E Picarella et al.

    Insulitis in transgenic mice expressing tumor necrosis factor β (lymphotoxin) in the pancreas

    Proc Natl Acad Sci USA

    (1992)
  • C.A Wilson et al.

    IL-1β modulation of spontaneous autoimmune diabetes and thyroiditis in the BB rat

    J Immunol

    (1990)
  • C.O Jacob et al.

    Prevention of diabetes in nonobese diabetic mice by tumor necrosis factor (TNF)Similarities between TNFα and interleukin-1

    Proc Natl Acad Sci USA

    (1990)
  • J. Zielasek et al.

    Interleukin-2-dependent control of disease development in spontaneously diabetic BB rats

    Immunology

    (1990)
  • M.J Rapoport et al.

    IL-4 reverses T-cell proliferative unresponsiveness and prevents the onset of diabetes in NOD mice

    J Exp Med

    (1993)
  • J. Satoh et al.

    Recombinant human tumor necrosis factor-α suppresses autoimmune diabetes in nonobese diabetic mice

    J Clin Invest

    (1989)
  • J. Satoh et al.

    Inhibition of type I diabetes in BB rats with recombinant human tumor necrosis factor-α

    J Immunol

    (1990)
  • H. Seino et al.

    Prevention of autoimmune diabetes with lymphotoxin in NOD mice

    Diabetes

    (1993)
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