Tumor necrosis factor α (TNF-α)-induced prostaglandin E2 release is mediated by the activation of cyclooxygenase-2 (COX-2) transcription via NFκB in human gingival fibroblasts

S. Nakao, Y. Ogtata, E. Shimizu, M. Yamazaki, S. Furuyama, H. Sugiya

Research output: Contribution to journalArticlepeer-review

Abstract

Nuclear factor kappB (NFκB) is a transcription factor and plays a key role in the expression of several genes involved in the inflammatory process. Cyclooxygenase (COX) is the key regulatory enzyme of the prostaglandin/eicosanoid synthetic pathway. COX-2 is a highly inducible enzyme by proinflammatory cytokines, of which gene expression is regulated by NFκB. TNF-α is a pro-inflammatory cytokine. In this paper, we investigated the involvement of NFκB on TNF-α-mediated prostaglandin E2 (PGE2) release and COX-2 gene expression in human gingival fibroblasts (HGF). TNF-α-induced PGE2 release and COX-2 mRNA accumulation in a time- and concentration-dependent manner in HGF. The results of transient transfection assays using a chimeric construct ofthe human COX-2 promoter (nts -1432 ∼ +59) ligated to a luciferase reporter gene indicated that TNF-α stimulated the transcriptional activity ∼ 1.4-fold. Gel mobility shift assays with a radiolabelled COX-2-NFκB oligonucleotide (nts -223 to -214) revealed an increase in the binding of nuclear proteins from TNF-α-stimulated HGE The COX-2-NFκB DNA-protein complex disappeared after treatment with pyrrolidine dithiocarbamate (PDTC; an antioxidant) or herbimycin A (a tyrosine kinase inhibitor). PDTC and herbimycin A attenuated TNF-α-stimulated PGE2 release. These results suggest that NFκB transcription factor is a key regulator of COX-2 expression in TNF-α-induced PGE2 production, which is mediated through a tyrosine kinase pathway in HGF.

Original languageEnglish (US)
Pages (from-to)11-18
Number of pages8
JournalMolecular and Cellular Biochemistry
Volume238
Issue number1-2
DOIs
StatePublished - Sep 2002

Keywords

  • COX-2
  • Gene regulation
  • Human gingival fibroblasts
  • NFκB
  • PGE
  • TNF-α

ASJC Scopus subject areas

  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

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