The directin vitroeffect of interleukin-6 (IL-6) on pancreatic beta-cells was studied using isolated Lewis rat islets (25/ml/well) precultured for 7 days and then incubated with or without human recombinant 1L-6 (rIL-6) or purified human natural IL-6 (nlL-6). Both sources of IL-6 stimulated insulin secretion over a period of 6 days (P<0.01). whereas the levels of insulin within the islets were unaffected. At concentrations above 1.5ng/ml, rIL-6 almost doubled the content of insulin in the supernatants. At an intermediate concentration, 0.5ng/ml, rIL-6 preserved insulin secretion by islets cocultured with 2ng/ml of human recombinant interleukin lβ(rIL-Iβ) which otherwise inhibited insulin secretion to 60% of islets cultured in medium alone. Electron microscopic studies showed that rIL-6, 1.5ng/ml, caused beta-cell specific degenerative changes similar to those previously described after treatment with IL-1β; i.e. appearance of opaque intracytoplasmic bodies, autophage vacuoles and signs of mitochondrial degeneration. We conclude that human IL-6 stimulates insulin production and secretionin virroand induces similar ultrastructural changes in beta-cells as does IL-Iβ. IL-6 may be an endogenous mediator of some of the effects on beta-cells ascribed to IL-1.