Cytokines and their roles in pancreatic islet beta-cell destruction and insulin-dependent diabetes mellitus.
Insulin-dependent diabetes mellitus (IDDM) is a disease that results from autoimmune destruction of the insulin-producing beta-cells in the pancreatic islets of Langerhans. The autoimmune response against islet beta-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 (IFNgamma), and tumor necrosis factor beta (TNFbeta), 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 beta-cell destruction. Type 1 cytokines activate (1) cytotoxic T cells that interact specifically with beta-cells and destroy them, and (2) macrophages to produce proinflammatory cytokines (IL-1 and TNFalpha), and oxygen and nitrogen free radicals that are highly toxic to islet beta-cells. Furthermore, the cytokines IL-1, TNFalpha, and IFNgamma are cytotoxic to beta-cells, in large part by inducing the formation of oxygen free radicals, nitric oxide, and peroxynitrite in the beta-cells themselves. Therefore, it would appear that prevention of islet beta-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.
Rabinovitch
A
A
Department of Medicine, University of Alberta, Edmonton, Canada.
Suarez-Pinzon
W L
WL
D015551:Autoimmunity; D016207:Cytokines / Q000276:immunology* / Q000502:physiology / Q000627:therapeutic use; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000473:pathology; D005609:Free Radicals; D006801:Humans; D007515:Islets of Langerhans / Q000276:immunology* / Q000473:pathology; D009569:Nitric Oxide / Q000502:physiology; D018417:Th1 Cells / Q000276:immunology
D016207:Cytokines; D005609:Free Radicals; D009569:Nitric Oxide