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

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.