Potential role of resident islet macrophage activation in the initiation of autoimmune diabetes. J Immunol 1998 Mar 15;160(6):2684-91
Date
03/24/1998Pubmed ID
9510167Scopus ID
2-s2.0-0032521025 (requires institutional sign-in at Scopus site) 134 CitationsAbstract
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.
Author List
Arnush M, Scarim AL, Heitmeier MR, Kelly CB, Corbett JAAuthor
John A. Corbett PhD Chair, Professor in the Biochemistry department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsDiabetes Mellitus, Type 1
Insulin
Interleukin-1
Islets of Langerhans
Lipopolysaccharides
Macrophage Activation
Male
Nitric Oxide
Nitric Oxide Synthase
Nitric Oxide Synthase Type II
Nitrites
Organ Culture Techniques
RNA, Messenger
Rats
Rats, Sprague-Dawley
Tumor Necrosis Factor-alpha
