AJP - Cell Physiology, Vol 267, Issue 1 C48-C54, Copyright © 1994 by American Physiological Society

ARTICLES

Tyrosine kinase involvement in IL-1 beta-induced expression of iNOS by beta-cells purified from islets of Langerhans

J. A. Corbett, G. Kwon, T. P. Misko, C. P. Rodi and M. L. McDaniel
Department of Pathology, Washington University School of Medicine, St. Louis 63110.

Nitric oxide is believed to mediate the inhibitory effects of cytokines on glucose-stimulated insulin secretion by both rat and human islets. The aims of this study were 1) to determine the cellular source of the cytokine-inducible isoform of nitric oxide synthase (iNOS) expressed in islets following cytokine stimulation and 2) to determine whether tyrosine kinase activity participates in cytokine-induced iNOS expression. In this report we demonstrate that the cytokine interleukin-1 beta (IL-1 beta) stimulates the expression of iNOS and the formation of nitric oxide (as determined by nitrite formation, a stable oxidative product of nitric oxide) by isolated intact rat islets and by primary beta-cells purified by fluorescence-activated cell sorting (FACS). Both the expression of iNOS and nitrite formation induced by IL-1 beta were prevented by the mRNA transcriptional inhibitor actinomycin D. IL-1 beta did not induce the expression of iNOS by FACS-purified alpha-cells, the other major endocrine cell type of the islet. The tyrosine kinase inhibitors genistein and herbimycin A prevented IL-1 beta-induced expression of immunoprecipitable iNOS and nitrite release by islets, by insulinoma RINm5F cells, and by FACS-purified beta-cells. Herbimycin A and genistein also prevented IL-1 beta-induced iNOS mRNA accumulation as determined by Northern blot analysis of total RNA isolated from RINm5F cells. These findings indicate tyrosine kinase activation participates in IL-1 beta-induced expression of iNOS by the insulin-secreting beta-cell.(ABSTRACT TRUNCATED AT 250 WORDS)

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