Signal transduction pathways of IL-1β-mediated iNOS in pulmonary vascular smooth muscle cells

Jonathan D. Finder, Jennifer L. Petrus, Andrew Hamilton, Raphael T. Villavicencio, Bruce R. Pitt, Saïd M. Sebti

Research output: Contribution to journalArticle

Abstract

Interleukin (IL)-1β is an important early mediator of inflammation in pulmonary artery smooth muscle cells. We previously reported that a geranylgeranyltransferase inhibitor elevated basal levels of inducible nitric oxide synthase (iNOS) and enhanced IL-1β-mediated induction, suggesting that Rac or Rho small G proteins are candidates for antagonism of such induction. In this study, overexpression of constitutively active Rac1 or its dominant negative mutant did not affect IL-1β induction of iNOS. Alternatively, treatment with Clostridium botulinum C3 exoenzyme, which ADP-ribosylates Rho, was associated with superinduction of iNOS, suggesting an inhibitory role for Rho. IL-1β activated the three mitogen-activated protein kinase (extracellular signal-regulated kinases 1 and 2, c-Jun NH2-terminal kinase/stress-activated protein kinase, and p38) and the Janus kinase (JAK)-signal transducer and activator of transcription pathways. The former two pathways were not associated with IL-1β-mediated iNOS induction, whereas the latter two appeared to have inhibitory roles in iNOS expression. These data suggest that a broad intracellular signaling response to IL-1β in rat pulmonary artery smooth muscle cells results in elevated levels of iNOS that is opposed by the geranylgeranylated small G protein Rho as well as the p38 and JAK2 pathways.

Original languageEnglish (US)
Pages (from-to)L816-L823
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume281
Issue number4 25-4
DOIs
StatePublished - 2001

Keywords

  • Inducible nitric oxide synthase
  • Interleukin-1β
  • Mitogen-activated protein kinase
  • Rho

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

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