Dexamethasone suppresses iNOS gene expression by upregulating I-κBα and inhibiting NF-κB

Michael E. De Vera, Bradley S. Taylor, Qi Wang, Richard A. Shapiro, Timothy R. Billiar, David A. Geller*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

112 Scopus citations


Cytokine-stimulated inducible nitric oxide synthase (iNOS) gene expression is dependent on nuclear factor-κB (NF-κB) activation and is suppressed by glucocorticoids (GC). In this study we examined the molecular mechanisms of GC inhibition of iNOS expression in rat hepatocytes. Combinations of tumor necrosis factor-α, interleukin-1β, and interferon-γ (cytokine mixture CM) induced high levels of iNOS mRNA and NO synthesis. The synthetic GC dexamethasone markedly repressed iNOS mRNA and protein expression, and nuclear run-on assays showed that this inhibition was occurring at the level of transcription. In addition, transfection studies showed that CM-stimulated activity of a 1.6-kb murine iNOS promoter fragment linked upstream of luciferase was suppressed by dexamethasone. Electromobility shift assays demonstrated that CM induced the appearance of an NF-κB complex composed of p50 and p65 subunits; the addition of dexamethasone markedly decreased this band shift. I-κBα expression was decreased by CM and upregulated in the presence of dexamethasone. Subsequently, nuclear p65 levels were decreased by dexamethasone compared with CM-treated cells. Thus GC repress NF-κB DNA-binding activity in rat hepatocytes in part through the upregulation of its inhibitor I-κBα. These data indicate that one mechanism by which GC block iNOS expression is through the inhibition of NF-κB activation resulting in decreased iNOS transcription.

Original languageEnglish
Pages (from-to)G1290-G1296
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Issue number6 36-6
StatePublished - 1997
Externally publishedYes


  • Gene regulation
  • Glucocorticoids
  • Inducible nitric oxide synthase
  • Interferon-γ
  • Interleukin-1β
  • Nuclear factor-κB
  • Tumor necrosis- α


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