LOW-DOSE INTERLEUKIN-1 AND TUMOR-NECROSIS-FACTOR INDIVIDUALLY STIMULATE INSULIN RELEASE BUT IN COMBINATION CAUSE SUPPRESSION

The macrophage-derived cytokines interleukin 1 (IL-1) and tumor necros is factor (TNF) have direct effects on pancreatic beta cells and have been hypothesized to play important roles in the autoimmune beta cell lesion of type I diabetes because of two major effects on beta cells: altered insulin secretion and beta cell cytotoxicity. High doses of IL -1 are cytotoxic to beta cells and strongly inhibit insulin release; h igh-dose IL-1 plus TNF acts synergistically to suppress further the in sulin release. In contrast, we observed that the predominant effect of low-dose IL-1 and TNF when administered separately was the stimulatio n of insulin release. We therefore asked whether the combination of lo w-dose IL-1 plus TNF would act synergistically to stimulate or suppres s insulin release. Studies were performed on cultured rat islets and b oth insulin release and cytotoxicity (Cr-51 release) were measured. Af ter 2 days of culture, increasing doses of IL-1-25, 50, 75 and 100 ng/ l-caused progressively increased cytotoxicity and impaired insulin rel ease. In contrast, the lowest dose of IL-1 tested, 10 ng/l, increased insulin release but was still slightly cytotoxic. Tumor necrosis facto r at doses of 10, 25, 62.5, 75 and 100 mu g/l also was slightly cytoto xic but increased insulin release. The augmented insulin release decli ned progressively with increasing TNF dose. However the combination of insulin stimulatory doses of IL-1 (10 ng/l) and TNF (62.5 mu g/l) sup pressed insulin release. The effects of these two cytokines on insulin release demonstrated a similar pattern after 4 and 6 days of culture. Although both IL-1 and TNF are cytotoxic to cultured islets cells, th e effects of these two cytokines on insulin release are markedly diffe rent; with IL-1 primarily suppressing and TNF increasing insulin relea se. In combination, IL-1 and TNF always inhibits insulin release. The lack of concordance between insulin release and cytotoxicity suggests that these cytokines may alter insulin release by at least two mechani sms, one dependent on and the other independent of cytotoxicity.