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This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: 297/5/L892    most recent 00151.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Yang, C.-M. Articles by Hsiao, L.-D. PubMed PubMed Citation Articles by Yang, C.-M. Articles by Hsiao, L.-D.

Cigarette smoke extract induces COX-2 expression via a PKC/c-Src/EGFR, PDGFR/PI3K/Akt/NF-B pathway and p300 in tracheal smooth muscle cells

¹Department of Pharmacology, Chang Gung University, and ; ²Departments of Anesthetics and ; ³Internal Medicine, Chang Gung University and Chang Gung Memorial Hospital, Kwei-San, Tao-Yuan; and ; ⁴Department of Physiology, National Yang Ming University, Taipei, Taiwan

Submitted 7 May 2009 ; accepted in final form 21 August 2009

Exposure to cigarette smoke extract (CSE) leads to airway or lung inflammation, which may be mediated through cyclooxygenase-2 (COX-2) expression and its product prostaglandin E₂ (PGE₂) synthesis. The aim of this study was to investigate the molecular mechanisms underlying CSE-induced COX-2 expression in human tracheal smooth muscle cells (HTSMCs). Here, we describe that COX-2 induction is dependent on PKC/c-Src/EGFR, PDGFR/PI3K/Akt/NF-B signaling in HTSMCs. CSE stimulated the phosphorylation of c-Src, EGFR, PDGFR, and Akt, which were inhibited by pretreatment with the inhibitor of PKC (Gö6976 or Gö6983), c-Src (PP1), EGFR (AG1478), PDGFR (AG1296), or PI3K (LY294002). Moreover, CSE induced a significant increase in COX-2 expression, which was reduced by pretreatment with these inhibitors or transfection with siRNA of PKC, Src, or Akt. Furthermore, CSE-stimulated NF-B p65 phosphorylation and translocation were also attenuated by pretreatment with Gö6976, PP1, AG1478, AG1296, or LY294002. CSE-induced COX-2 expression was also mediated through the recruitment of p300 associated with NF-B in HTSMCs, revealed by coimmunoprecipitation and Western blot analysis. In addition, pretreatment with the inhibitors of NF-B (helenalin) and p300 (garcinol) or transfection with p65 siRNA and p300 siRNA markedly inhibited CSE-regulated COX-2 expression. However, CSE-induced PGE₂ generation was reduced by pretreatment with the inhibitor of COX-2 (NS-398). These results demonstrated that in HTSMCs, CSE-induced COX-2-dependent PGE₂ generation was mediated through PKC/c-Src/EGFR, PDGFR/PI3K/Akt leading to the recruitment of p300 with NF-B complex.

cyclooxygenase-2; prostaglandin E₂; airway inflammation; human