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Am J Physiol Lung Cell Mol Physiol 281: L816-L823, 2001;
1040-0605/01 $5.00
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Vol. 281, Issue 4, L816-L823, October 2001

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

Jonathan D. Finder1, Jennifer L. Petrus1, Andrew Hamilton2, Raphael T. Villavicencio3, Bruce R. Pitt4, and Saïd M. Sebti5

Departments of 1 Pediatrics, 3 Surgery, and 4 Environmental and Occupational Health, University of Pittsburgh School of Medicine and Graduate School of Public Health, Pittsburgh, Pennsylvania 15261; 5 Drug Discovery Program, H. Lee Moffitt Cancer Center, Department of Biochemistry and Molecular Biology, University of South Florida, Tampa, Florida 33612; and 2 Department of Chemistry, Yale University, New Haven, Connecticut 06520

Interleukin (IL)-1beta 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-1beta -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-1beta 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-1beta 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-1beta -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-1beta 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.

inducible nitric oxide synthase; interleukin-1beta ; Rho; mitogen-activated protein kinase


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