INTRODUCTION Cytokines have been suggested to cause pancreatic β-cell destruction in the autoimmune process leading to insulin-dependent diabetes mellitus. 1,2 Particularly interleukin 1 (IL-1) has been found to impair or even to kill rodent β-cells in vitro. 3–5 Important features of the events leading to this, is binding of IL-1 to a surface receptor, gene expression including induction of the enzyme nitric oxide synthase, formation of nitric oxide, impairment of mitochondrial glucose metabolism and a lowered ATP production. Insulin-producing cells seems to possess an inducible form of nitric oxide syn- thase, which is similar to that observed in cytokine acti- vated macrophages. 6 In this context the cytokine interleukin 4 (IL-4) might be of special interest since it has been found to modulate the induction nitric oxide synthase in macrophages. 7 Moreover, IL-4 has been shown to stimulate expression of IL-1 receptor an- tagonist mRNA in both resting and activated macrophages. 8 Otherwise IL-4 has been proposed to promote Th2 cells and B cell development during an immune response. 9 The aim of the present study was to study if exposure of IL-4 influences the function of pan- creatic β-cells and whether IL-4 affects the action of IL- 1β on islet cells. For this purpose isolated rat pancreatic islets were exposed in tissue culture to different con- centrations of human IL-4 in the absence or presence of IL-1β, and subsequently islet insulin and DNA con- tents, nitrite accumulation, rates of glucose oxidation and (pro)insulin and total protein biosynthesis and glu- cose-stimulated insulin secretion were measured. RESULTS AND DISCUSSION The medium insulin accumulation of the control group, i.e. islets cultured in medium not supplemented with any cytokine was 5.7 6 0.8 ng insulin/islet 3 1 h. Addition of IL-1β caused a marked reduction in medium insulin accumulation to 3.0 6 0.7 (n 5 14 in both groups; P , 0.001). IL-4 (0.1–10 ng/ml) did not sig- nificantly influence the medium insulin accumulation compared to the control group, either alone or after IL-1β addition (data not shown). The islet cell number, as reflected in the DNA content, tended to be reduced by IL-1β and this effect became significant when all three concentrations of IL-4 were present together with IL-1β (Fig. 1). At 0.1 ng/ml IL-4 itself caused a slight decrease in the islet DNA content. The islet insulin con- tent was not significantly affected by IL-4, whilst IL-1β caused a 30% decline (Fig. 2). The (pro)insulin and the total protein biosynthesis rate was not changed by IL- 296 CYTOKINE, Vol. 7, No. 3 (April), 1995: pp 296–300 INTERLEUKIN 4 IMPAIRS RAT PANCREATIC ISLET FUNCTION IN VITRO BY AN ACTION DIFFERENT TO THAT OF INTERLEUKIN 1 Stellan Sandler, Johnny Sternesjö Cytokines, in particular interleukin 1 (IL-1 ), have been implicated in pancreatic -cell destruction in insulin-dependent diabetes mellitus. In the rat prolonged exposure in vitro of islets of IL-1 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 for- mation in other cell systems. In the present study we have investigated the effect of IL-4 alone and in combination with IL-1 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 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 -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 stimulation of medium nitrite was partly reduced by IL-4. Compared to the action exerted by IL-1 the inhibitory action of IL-4 on rat islet function was moderate, and the latter action seems to be independent on nitric oxide production. From the Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden Correspondence to: Dr Stellan Sandler, Department of Medical Cell Biology, Biomedicum, P.O. Box 571, S-751 23 Uppsala, Sweden Received 27 May 1994; accepted for publication 28 September 1994 © 1995 Academic Press Limited 1043-4666/95/03029615 $08.00/0 KEY WORDS: β-cells/interleukin 1/interleukin 4/Nitric oxide/ pancreatic islets