DIFFERENTIAL-EFFECTS OF CYTOKINES ON LONG-TERM MITOGENIC AND SECRETORY RESPONSES OF FETAL-RAT PANCREATIC BETA-CELLS

It has been proposed that certain cytokines secreted by islet-infiltrating leukocytes may be involved in the pathogenesis of insulin-dependent diabetes mellitus by participation in beta-cell destruction. In the present study, the impact of various cytokines on replication and long-term insulin secretion by pancreatic beta-cells was investigated. To this end, fetal rat pancreatic islets containing a high fraction of beta-cells were exposed in culture for 1-3 days to interleukin-1-beta (IL-1-beta), tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), interferon-alpha (IFN-alpha), and interleukin-6 (IL-6) at different concentrations. It was found that IL-1-beta markedly decreased beta-cell DNA synthesis during the first day of exposure, an effect that vanished after 2 days and was turned into a potent and dose-dependent stimulation by 3 days of exposure. At this latter time point, IL-1-beta also amplified the mitogenicity of growth hormone (GH) and 16.7 mM glucose. In contrast, basal as well as glucose- and GH-stimulated insulin secretion was consistently suppressed by IL-1-beta from days 1-3. IL-1-beta also lowered the islet adenosine 3',5'-cyclic monophosphate (cAMP) content at all time points studied. However, addition of the stimulatory cAMP analogue Sp-diastereomer of adenosine 3',5'-cyclic monophosphothioate or pertussis toxin, which themselves enhanced DNA synthesis and insulin secretion, failed to prevent the inhibitory actions of IL-1-beta on these parameters, making it unlikely that a decrease in cAMP is an important event in transduction of the inhibitory effects of the cytokine. IFN-gamma caused a modest, but significant, enhancement of beta-cell replication but impeded insulin secretion in response to glucose and GH. TNF-alpha, IFN-alpha, and IL-6 did not affect beta-cell replication or insulin secretion except for a slight elevation of the rate of long-term insulin secretion induced by IL-6. It is concluded that certain cytokines can exert both inhibitory and stimulatory long-term actions on pancreatic beta-cell replication and insulin secretion. These direct effects on the beta-cell may influence the clinical outbreak and course of diabetes mellitus.