Endocrinology, Vol 137, 825-830, Copyright © 1996 by Endocrine Society

ARTICLES

Interleukin 1-induced Fos and Jun do not regulate inducible nitric oxide synthase in rat islets of Langerhans and RINm5F cells

G Kwon, JA Corbett and ML McDaniel
Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110-8118, USA.

Recent evidence indicates that nitric oxide (NO) produced after expression of inducible NO synthase (iNOS) mediates cytokine-induced inhibition of insulin secretion by pancreatic islets. The current studies were designed to characterize the involvement of immediate- early response genes, c-fos and c-jun, in interleukin 1 (IL-1)-induced expression of iNOS. iNOS messenger RNA (mRNA) expression by both rat islets and RINm5F cells was time dependent, with maximal expression observed after an approximately 3- to 6-h exposure to IL-1. IL-1 also stimulated rapid and transient expression of c-fos and c-jun by both rat islets and RINm5F cells, with maximal mRNA accumulation detected 30- 60 min after IL-1 treatment. IL-1-induced protein synthesis of Fos and Jun was observed as early as 30 min, peaked between 3-5 h, and decreased by 8 h after IL-1 treatment. Temporal correlation of Fos and Jun expression and iNOS gene induction suggested that Fos and Jun might regulate iNOS gene transcription by rodent pancreatic beta-cells. The present study, however, indicates that IL-1 induced expression of Fos and Jun does not seem to participate in the regulation of iNOS and mRNA expression, because: 1) cycloheximide (1 microM) completely inhibited Fos expression but had no inhibitory effect on iNOS mRNA levels; and 2) tyrosine kinase inhibitors genistein and herbimycin A completely inhibited IL-1 induced iNOS expression but did not block c-fos and c- jun expression. These results indicate that two separate signaling pathways may exist for induction of c-fos and c- jun and iNOS genes and that de novo synthesis of Fos and Jun does not participate in the regulation of iNOS gene expression.

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