Arnush M, Scarim A L, Heitmeier M R, Kelly C B, Corbett J A
Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, MO 63104, USA.
J Immunol. 1998 Mar 15;160(6):2684-91.
The purpose of this study was to evaluate the effects of resident islet macrophage activation on beta cell function. Treatment of freshly isolated rat islets with TNF-alpha and LPS results in a potent inhibition of glucose-stimulated insulin secretion. The inhibitory actions of TNF + LPS are mediated by the intraislet production and release of IL-1 followed by IL-1-induced inducible nitric oxide synthase (iNOS) expression by beta cells. The IL-1R antagonist protein completely prevents TNF + LPS-induced nitrite production, iNOS expression and the inhibitory effects on glucose-stimulated insulin secretion by rat islets. Resident macrophages appear to be the source of IL-1, as a 7-day culture of rat islets at 24 degrees C (conditions known to deplete islets of lymphoid cells) prevents TNF + LPS-induced iNOS expression, nitrite production, and the inhibitory effects on insulin secretion. In addition, macrophage depletion also inhibits TNF + LPS-induced IL-1alpha and IL-1beta mRNA expression in rat islets. Immunocytochemical colocalization of IL-1beta with the macrophage-specific marker ED1 was used to provide direct support for resident macrophages as the islet cellular source of IL-1. IL-1beta appears to mediate the inhibitory actions of TNF + LPS on beta cell function as TNF + LPS-induced expression of IL-1beta is fourfold higher than IL-1alpha, and Ab neutralization of IL-1beta prevents TNF + LPS-induced nitrite production by rat islets. These findings support a mechanism by which the activation of resident islet macrophages and the intraislet release of IL-1 may mediate the initial dysfunction and destruction of beta cells during the development of autoimmune diabetes.
本研究的目的是评估胰岛内常驻巨噬细胞激活对β细胞功能的影响。用肿瘤坏死因子-α（TNF-α）和脂多糖（LPS）处理新鲜分离的大鼠胰岛，会导致葡萄糖刺激的胰岛素分泌受到强烈抑制。TNF + LPS的抑制作用是由胰岛内白细胞介素-1（IL-1）的产生和释放介导的，随后β细胞会因IL-1诱导而表达诱导型一氧化氮合酶（iNOS）。IL-1受体拮抗剂蛋白可完全阻止TNF + LPS诱导的亚硝酸盐生成、iNOS表达以及对大鼠胰岛葡萄糖刺激的胰岛素分泌的抑制作用。常驻巨噬细胞似乎是IL-1的来源，因为在24℃下对大鼠胰岛进行7天培养（已知该条件可使胰岛中的淋巴细胞耗竭）可阻止TNF + LPS诱导的iNOS表达、亚硝酸盐生成以及对胰岛素分泌的抑制作用。此外，巨噬细胞耗竭也会抑制TNF + LPS诱导的大鼠胰岛中IL-1α和IL-1β mRNA表达。使用IL-1β与巨噬细胞特异性标志物ED1的免疫细胞化学共定位，为常驻巨噬细胞作为胰岛细胞中IL-1的来源提供了直接支持。IL-1β似乎介导了TNF + LPS对β细胞功能的抑制作用，因为TNF + LPS诱导的IL-1β表达比IL-1α高四倍，并且用抗体中和IL-1β可阻止TNF + LPS诱导的大鼠胰岛亚硝酸盐生成。这些发现支持了一种机制，即胰岛内常驻巨噬细胞的激活和IL-1在胰岛内的释放可能在自身免疫性糖尿病发展过程中介导β细胞的初始功能障碍和破坏。
