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Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO 63104
The purpose of this study was to evaluate the effects of resident
islet macrophage activation on ß cell function. Treatment of freshly
isolated rat islets with TNF-
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 ß 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°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-1 and IL-1ß mRNA expression in rat islets.
Immunocytochemical colocalization of IL-1ß with the
macrophage-specific marker ED1 was used to provide direct support for
resident macrophages as the islet cellular source of IL-1. IL-1ß
appears to mediate the inhibitory actions of TNF + LPS on ß cell
function as TNF + LPS-induced expression of IL-1ß is fourfold
higher than IL-1, and Ab neutralization of IL-1ß 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 ß cells during the development of autoimmune
diabetes.
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