Exp Mol Med.  2003 Jun;35(3):175-180.

Induction of nitric oxid esynthase(NOS) by soluble glucocorticoid induced tumor necrosis factor receptor(sGITR) is modulated by IFN-g in murine macrophage

• Shin HH
• Lee HW
• Choi HS

Abstract

Earlier study showed that glucocorticoid induced tumor necrosis factor receptor (GITR), a new TNFR family, activated murine macrophages to express inducible nitric oxide synthase (iNOS) and to generate nitric oxide (NO). A possible involvement of pro-inflammatory cytokines on NO production by GITR was investigated in vitro systems and signaling molecules contributing to sGITR-induced iNOS production are determined in Raw 264.7 cells, a murine macrophage cell line. The result showed that the synergy was afforded by the combination of GITR with IFN-gamma in a dose-dependent manner but IFN-gamma alone was not able to induce NOS. No effects were observed with TNF-alpha, IL-1beta, or IL-6 co-treated with GITR. To determine signaling molecules contributing to sGITR-induced iNOS production, a specific inhibitor for signal pathway proteins tested showed that PDTC (NF- kB) and genistein (tyrosine kinase) inhibited NOS induction significantly, while sodium orthovanadate (tyrosine phosphatase) potentiated NOS expression. These results suggest that activations of NF-kB were involved in induction of iNOS by GITR and IFN-gamma priming caused earlier and stronger NF-kB activation.

Keyword

glucocorticoids; interferon type II; marophages; nitric oxide; nitric-oxide synthase; receptors, tumor necrosis factor

MeSH Terms

Animals
Cells, Cultured
Cytokines/*metabolism
Enzyme Induction
Interferon Type II/pharmacology
Macrophages/*enzymology/physiology
Mice
NF-kappa B/metabolism
Nitric Oxide/metabolism
Nitric-Oxide Synthase/*biosynthesis
Protein-Tyrosine Kinase/metabolism
Protein-Tyrosine-Phosphatase/metabolism
Receptors, Nerve Growth Factor/*metabolism
Receptors, Tumor Necrosis Factor/*metabolism