INVOLVEMENT OF INTERLEUKIN-1 AND INTERLEUKIN-1 ANTAGONIST IN PANCREATIC BETA-CELL DESTRUCTION IN INSULIN-DEPENDENT DIABETES-MELLITUS

In this review we propose that the balance between the action of interleukin 1 (IL-1) and its natural antagonist IL-1ra on the level of the insulin-producing pancreatic β-cell may play a decisive role in the pathogenesis of insulin-dependent diabetes mellitus (IDDM). We argue that IL-1 potentiated by other cytokines (tumor necrosis factor α, interferon gamma) is an important effector molecule involved in both early and late events in the immune-mediated process that leads to β-cell destruction and IDDM. We also point out that surprisingly high molar excesses of IL-1ra over IL-1 are necessary to block the action of IL-1 on islet β-cells compared to islet α-cells in vitro and in animals. We suggest that the selectivity of β-cell destruction in IDDM may be conferred on several levels: (1) homing of β-cell antigen specific T cells, (2) targeted delivery of cytokines by lymphocytic and monocytic cells to β-cells, (3) high molar excesses of IL-1ra over IL-1 needed to prevent IL-1 mediated β-cell toxicity, (4) increased β-cell sensitivity to free nitric oxide and oxygen radical formation induced by IL-1 and (5) inadequate oxidative stress response by β-cells to cytokines. Further studies are needed to establish the in vivo role of an imbalance between the amounts of IL-1 and IL-1ra produced relative to their action in the pathogenesis of IDDM. © 1993 Academic Press Limited.