Effects of Activated Macrophages on Islet Function

EFFECTS OF ACTIVATED MACROPHAGES ON ISLET FUNCTION 

PROPOSED MECHANISM BY WHICH INTERLEUKIN 1 INDUCES /3-CELL DYSFUNCTION AND DESTRUCTION 

We have proposed a mechanism by which lL-1 exerts its deleterious effects on islet function and viability (Fig. 11 Corbett et al., 1992). In this proposed mechanism, lL-1 is released by macrophages during the initial stages of islet infiltration. IL-1 binds to a specific IL-1 receptors on the /3 cell activating a tyrosine kinase. Tyrosine kinase phosphorylation stimulates second messengers to induce the expression of c-/os, c-jun, the activation of NF-xB, and possibly other early transcriptional regulators. These early-immediate transcriptional response elements may activate or stimulate the expression of inducible nitric oxide 

Proposed model of IL-l-induced inhibition of glucose-stimulated insulin secretion and islet destruc- 

IDDM is a disease in which /3 cells of islets are selectively destroyed. How does a nonspecific effector molecule (nitric oxide) mediate the selective destruction of the /3 cell We propose that the specificity of cytokine interactions with the /8 cell, and the intrinsic sensitivity of the /3 cell to oxidative damage relative to other endocrine cells may impart this selective destruction. In rats the effects of lL-1 appear to be specific to the /3 cell. lL-1 induces iNOS expression and the overproduction of nitric oxide by /3 cells, but does not induce expression of iNOS or nitric oxide formation in other islet endocrine or nonendocrine cells of the 

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VIII. EFFECTS OF ACTIVATED MACROPHAGES ON ISLET FUNCTION... 

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