POTENTIAL ROLE OF RESIDENT ISLET MACROPHAGE ACTIVATION IN THE INITIATION OF AUTOIMMUNE DIABETES

The purpose of this study was to evaluate the effects of resident isle t macrophage activation on beta cell function, Treatment of freshly is olated rat islets with TNF-alpha and LPS results in a potent inhibitio n of glucose-stimulated insulin secretion. The inhibitory actions of T NF + LPS are mediated by the intraislet production and release of IL-1 followed by IL-1-induced inducible nitric oxide synthase (iNOS) expre ssion by beta cells, The IL-1R antagonist protein completely prevents TNF + LPS-induced nitrite production, iNOS expression and the inhibito ry effects on glucose-stimulated insulin secretion by rat islets, Resi dent macrophages appear to be the source of IL-1, as a 7-day culture o f rat islets at 24 degrees C (conditions known to deplete islets of ly mphoid cells) prevents TNF + LPS-induced iNOS expression, nitrite prod uction, and the inhibitory effects on insulin secretion, In addition, macrophage depletion also inhibits TNF + LPS-induced IL-1 alpha and IL -1 beta mRNA expression in rat islets, Immunocytochemical colocalizati on of IL-1 beta with the macrophage-specific marker ED1 was used to pr ovide direct support for resident macrophages as the islet cellular so urce of IL-1, IL-1 beta appears to mediate the inhibitory actions of T NF + LPS on beta cell function as TNF + LPS-induced expression of IL-1 beta is fourfold higher than IL-1 alpha, and Ab neutralization of IL- 1 beta prevents TNF + LPS-induced nitrite production by rat islets, Th ese findings support a mechanism by which the activation of resident i slet macrophages and the intraislet release of IL-1 may mediate the in itial dysfunction and destruction of beta cells during the development of autoimmune diabetes.