Interleukin 1-induced Fos and Jun do not regulate inducible nitric oxide synthase in rat islets of Langerhans and RINm5F cells.
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.
Kwon
G
G
Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110-8118, USA.
Corbett
J A
JA
McDaniel
M L
ML
D000818:Animals; D002478:Cells, Cultured; D015971:Gene Expression Regulation, Enzymologic; D007375:Interleukin-1 / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000378:metabolism*; D008297:Male; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015533:Transcriptional Activation
D007375:Interleukin-1; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D019001:Nitric Oxide Synthase