Nitric oxide supresses inducible nitric oxide synthase expression by inhibiting post-translational modification of IκB

Kwang Chang, Seon Jin Lee, Ilyoung Cheong, Timothy R. Billiar, Hun Taeg Chung, Jeong A. Han, Young Guen Kwon, Kwon Soo Ha, Young Myeong Kim*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

65 Scopus citations


The expression of inducible nitric oxide synthase (iNOS) is a critical factor in both normal physiological functions and the pathogenesis of disease. This study was undertaken to determine the molecular mechanism by which nitric oxide (NO) exerts negative feedback regulation on iNOS gene expression. Isolated rat hepatocytes stimulated with cytokines exhibited a marked increase in NO production as well as iNOS mRNA and protein levels, which were significantly reduced by pretreatment of the NO donors S-nitroso-N-acetyl-D,L-penicillamine (SNAP) and V-PYRRO/NO. This effect of SNAP was inhibited when NO was scavenged using red blood cells. Pretreatment with oxidized SNAP, 8-Br-cGMP, NO 2-, or NO3- did not suppress the cytokine-induced NO production. Moreover, LPS/IFN-γ-stimulated RAW264.7 cells, which produce endogenous NO, expressed lower levels of iNOS, IL-1β, IL-6 and TNF-α mRNAs, without changes in their mRNA half-lives, than those in the presence of the iNOS inhibitor NG-monomethyl-L-arginine. The iNOS gene transcription rate exhibited an 18-fold increase after cytokine stimulation, which was significantly inhibited by SNAP pretreatment. SNAP also blocked cytokine-induced increase in NF-κB activation, iNOS promoter activity, nuclear translocation of cytosolic NF-κB p65 subunit, and IκBα degradation, which correlated with its inhibitory effect on phosphorylation and ubiquitination of IκB. These data indicate that NO down-regulates iNOS gene expression and NO production by inhibiting the post-translational processes of IκBα thereby preventing NF-κB activation. These results identify a novel negative feedback mechanism whereby NO down-regulates iNOS gene expression.

Original languageEnglish
Pages (from-to)311-324
Number of pages14
JournalExperimental and Molecular Medicine
Issue number4
StatePublished - 31 Aug 2004
Externally publishedYes


  • Feedback inhibition
  • Hepatocytes
  • Inducible nitric oxide synthase
  • IκB
  • NF-κB
  • Nitric oxide


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