Differential modulation by exogenous carbon monoxide of TNF-α stimulated mitogen-activated protein kinases in rat pulmonary artery endothelial cells

Jigme M. Sethi, Leo E. Otterbein, Augustine M K Choi

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

Heme oxygenase-1 (HO-1) is an enzyme that is highly inducible by various cellular stressors, especially oxidant injury. Our laboratory and others have demonstrated that induction of HO-1 exerts an antiinflammatory effect both in vitro and in vivo. We hypothesized that carbon monoxide (CO), a major catalytic by-product of heme catalysis by HO-1, may mediate this antiinflammatory effect by modulating signal transduction pathways, in particular the mitogen-activated protein (MAP) kinase pathway. Confluent primary cultures of rat pulmonary artery endothelial cells (RPAEC) were treated with tumor necrosis factor-α (TNF-α; 50 ng/ml), and whole-cell extracts were assayed for phosphorylated ERK1/2, JNK1/2, and p38 MAP kinases. These three major MAP kinase pathways were activated by TNF-α in a time-dependent manner. RPAEC treated with TNF-α in the presence of a low concentration of CO (1%) exhibited marked attenuation of the phosphorylation of ERK1/2 MAP kinase when compared with cells treated with TNF-α alone. A similar effect was seen on the upstream MEK 1/2 kinase. Interestingly, CO (1%) accentuated TNF-α-induced phosphorylated p38 MAP kinase. These effects of exogenous CO on the ERK1/2 and p38 systems could be replicated by overexpression of HO-1 in RPAEC, using an adenoviral vector. As these MAP kinases are implicated in the regulation of various inflammatory molecules and adhesion molecules, our data provide a potential mechanism by which HO-1, acting via CO, may modulate the inflammatory response by differential activation of the MAP kinase pathway.

Original languageEnglish (US)
Pages (from-to)241-248
Number of pages8
JournalAntioxidants and Redox Signaling
Volume4
Issue number2
DOIs
StatePublished - Jan 1 2002

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

Fingerprint Dive into the research topics of 'Differential modulation by exogenous carbon monoxide of TNF-α stimulated mitogen-activated protein kinases in rat pulmonary artery endothelial cells'. Together they form a unique fingerprint.

Cite this