Cytokines, in particular interleukin 1 beta (IL-1 beta), have been implicated in pancreatic beta-cell destruction in insulin-dependent diabetes mellitus. In the rat prolonged exposure in vitro of islets of IL-1 beta leads to nitric oxide formation, impaired glucose metabolism and inhibition of insulin secretion. Interleukin 4 (IL-4) has been shown to be able to modulate nitric oxide formation in other cell systems. In the present study we have investigated the effect of IL-4 alone and in combination with IL-1 beta on islet cells. For this purpose isolated rat pancreatic islets were cultured for 42 h in medium supplemented with 0, 0.1, 1.0 or 10 ng/ml of human IL-4 in the absence or presence of 25 U/ml of IL-1 beta during the last 24 h of culture. IL-4 alone dose-dependently decreased the islet glucose oxidation rate and the glucose-stimulated insulin release. Furthermore, the cytokine potentiated IL-1 beta-induced reduction in the islet DNA content and (pro)insulin biosynthesis rate. The medium nitrite accumulation, as an index of nitric oxide formation, was not influenced by IL-4 (10 ng/ml) alone, whilst IL-1 beta stimulation of medium nitrite was partly reduced by IL-4. Compared to the action exerted by IL-1 beta the inhibitory action of IL-4 on rat islet function was moderate, and the latter action seems to be independent on nitric oxide production.