A natural interleukin 1 (IL-1) inhibitor counteracts the inhibitory effect of IL-1 on insulin production in cultured rat pancreatic islets.

Several lines of evidence suggest that autoimmune processes are involved in the pathogenesis of Type I diabetes mellitus. Monocyte-macrophages are among the first mononuclear cells to invade the islets of Langerhans in various murine diabetic syndromes, and blockade of monocyte-macrophage functions by injection of silica particles in these animals prevents the development of the disease. Monokines such as interleukin 1 (IL-1) are known to mediate tissue lesions by inducing collagenase and prostaglandin E2 (PGE2) production. In addition, IL-1 has been demonstrated to inhibit proinsulin biosynthesis and secretion in pancreatic islet cells. Using 3-d cultured rat islets we have found that (a) the lowering of insulin release induced by human recombinant IL-1 (rIL-1) is dose-dependent with a decrease to 21% of control value at the higher rIL-1 tested concentration (500 pg/ml), and about two times more pronounced than the decrease in cellular insulin content, which reached 44% of control value at the highest rIL-1 concentration; (b) rIL-1 stimulates islets to secrete PGE2 but the addition of indomethacin, which blocks PGE2 production, does not affect the decrease in insulin release and content caused by IL-1, suggesting a limited role of endogenous PGE2 as a mediator in this system; and (c) a specific, noncytotoxic IL-1 inhibitor, shown in other cell systems to block the binding of IL-1 to its receptor, prevents the rIL-1 lowering of insulin content and minimizes the decrease of insulin release.