Amplification of nitric oxide synthase expression by nitric oxide in interleukin 1 beta-stimulated rat mesangial cells.
Nitric oxide (NO) plays an important role in immunological reactions as a host defense mechanism against tumor cells and invasive microorganisms, but it may also damage healthy tissue. The excessive formation of NO in IL-1 beta-stimulated renal mesangial cells not only alters glomerular filtration, but it may also cause tissue injury and thus contribute to the pathogenesis of certain forms of glomerulonephritis. We report here that, although NO alone has no evident effect on NO synthase expression, it potently augments IL-1 beta-stimulated NO synthase expression in mesangial cells. NO donors such as sodium nitroprusside and S-nitroso-N-acetyl-D,L-penicillamine markedly increase IL-1 beta-induced NO synthase mRNA and protein levels as well as enzyme activity. Nuclear run-on experiments suggest that NO acts to increase IL-1 beta-induced NO synthase gene expression at the transcriptional level. Furthermore, inhibition of NO synthesis by different pharmacological approaches reduces IL-1 beta-induced NO synthase expression, thus suggesting that NO functions in a positive feedback loop that speeds up and strengthens its own biosynthesis. We suggest that this potent amplification mechanism forms the basis for the excessive formation of NO in acute and chronic inflammatory diseases.
Mühl
H
H
Department of Pharmacology, University of Basel, Switzerland.
Pfeilschifter
J
J
D000594:Amino Acid Oxidoreductases / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D015152:Blotting, Northern; D002467:Cell Nucleus / Q000378:metabolism; D002956:Citrulline / Q000032:analysis; D015971:Gene Expression Regulation, Enzymologic; D005920:Glomerular Mesangium / Q000187:drug effects*; D007375:Interleukin-1 / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009569:Nitric Oxide / Q000494:pharmacology*; D019001:Nitric Oxide Synthase; D009573:Nitrites / Q000032:analysis; D009599:Nitroprusside / Q000494:pharmacology; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D026423:S-Nitroso-N-Acetylpenicillamine; D013997:Time Factors; D014158:Transcription, Genetic; D019323:omega-N-Methylarginine
D007375:Interleukin-1; D009573:Nitrites; D012333:RNA, Messenger; D009599:Nitroprusside; D019323:omega-N-Methylarginine; D002956:Citrulline; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D010396:Penicillamine