DIFFERENTIAL INTERLEUKIN-1 RECEPTOR ANTAGONISM ON PANCREATIC BETA-CELLS AND ALPHA-CELLS - STUDIES IN RODENT AND HUMAN ISLETS AND IN NORMAL RATS

The monokines interleukin-1alpha and -beta have been implicated as eff ector molecules in the immune-mediated pancreatic beta-cell destructio n leading to insulin-dependent diabetes mellitus. Here we investigated the effects of interleukin-1 receptor antagonism on insulin and gluca gon release of rat, mouse and human islets exposed to recombinant huma n interleukin-1beta, and on interleukin-1beta induced changes in blood glucose, serum insulin and serum glucagon levels in Wistar Kyoto rats . The interleukin-1 receptor antagonist reduced the co-mitogenic effec t of interleukin-1beta on mouse and rat thymocytes with a 50 % inhibit ory concentration of 10- and 100-fold molar excess, respectively. Comp lete inhibition was obtained with a 100-1,000-fold molar excess. Howev er, at a 100-fold molar excess the interleukin-1 receptor antagonist d id not antagonise the potentiating effect of interleukin-1beta on rat islet insulin accumulation during 3 and 6 h of exposure or of interleu kin-1beta-induced inhibition of insulin release after 24 h. In contras t, interleukin-1beta-stimulated islet glucagon release was completely antagonised by a 100-fold molar excess of interleukin-1 receptor antag onist. A 10,000-fold molar excess of interleukin-1 receptor antagonist was needed to antagonise interleukin- 1,8 stimulatory and inhibitory effects on rat beta-cell function in vitro. A 100-fold excess of inter leukin-I receptor antagonist could not counteract interleukin-1beta ef fects on mouse and human beta cells, excluding species difference in t he efficacy of the human interleukin-1 receptor antagonist. An anti-mo use interleukin-1 receptor type I antibody completely abolished interl eukin-1beta effects on isolated mouse islets. A 10-100-fold molar exce ss of interleukin-1 receptor antagonist antagonised interleukin-1beta- induced fever, hypercorticosteronaemia and hyperglucagonaemia, but not interleukin-1beta-induced reduction in insulin/glucose ratio in norma l rats. In conclusion, our results suggest that antagonism of interleu kin-1beta effects on beta cells requires higher concentrations of inte rleukin-1 receptor antagonist than those necessary to block interleuki n-1 action on islet alpha cells and other interleukin-I targets in vit ro and in vivo. This may contribute to the understanding of the specif icity of the immunological beta-cell destruction leading to insulin-de pendent diabetes.