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Differential modulation of COX-2 expression in A549 airway epithelial cells by structurally distinct PPARγ agonists: evidence for disparate functional effects which are independent of NF-κB and PPARγ

Patel, Kajal M. and Wright, Karen L. and Whittaker, Paul and Chakravarty, Probir and Watson, Malcolm L. and Ward, Stephen G. (2005) Differential modulation of COX-2 expression in A549 airway epithelial cells by structurally distinct PPARγ agonists: evidence for disparate functional effects which are independent of NF-κB and PPARγ. Cellular Signalling, 17 (9). pp. 1098-1110. ISSN 0898-6568

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Abstract

Ligands of peroxisome proliferator-activated receptor-γ (PPARγ) are thought to possess anti-inflammatory properties mediated via both PPARγ dependent and independent mechanisms. This work investigates the effects of PPARγ ligands on the regulation of cyclooxygenase-2 (COX-2) in the human lung epithelial cell line, A549. The synthetic ligand troglitazone activated the phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase pathway (MAPK), whereas the endogenous ligand, 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), only activated the PI3K pathway. 15d-PGJ2 had no detectable effects on COX-2, mPGES expression, or PGE2 production. However, troglitazone induced time-dependent COX-2 expression, which was insensitive to PPARγ antagonists, but was abrogated by inhibitors of PI3K and the ERK MAP kinase pathway. Furthermore, troglitazone induced mPGES expression and PGE2 production. Neither troglitazone nor 15d-PGJ2 was able to convincingly activate NF-κB in A549 cells. Further heterogeneity in the responses to troglitazone and 15d-PGJ2 was observed in the regulation of gene expression as assessed by microarray analysis. In summary, this study provides compelling evidence that troglitazone (like 15d-PGJ2) can exert functional effects independently of actions via PPARγ. Moreover, we have identified unique biochemical and functional actions of troglitazone that are not shared by 15d-PGJ2, which may influence the therapeutic potential of this compound in inflammatory settings.

Item Type: Article
Journal or Publication Title: Cellular Signalling
Uncontrolled Keywords: Cell activation ; Lung ; Transcription factors and signal transduction
Subjects: R Medicine > RM Therapeutics. Pharmacology
Departments: Faculty of Health and Medicine > Biomedical & Life Sciences
ID Code: 40891
Deposited By: Mr Richard Ingham
Deposited On: 16 Jun 2011 10:18
Refereed?: Yes
Published?: Published
Last Modified: 26 Jul 2012 18:06
Identification Number:
URI: http://eprints.lancs.ac.uk/id/eprint/40891

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