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J. Biol. Chem., Vol. 280, Issue 4, 2550-2561, January 28, 2005

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Differential Regulation of Chemokine Expression by Peroxisome Proliferator-activated Receptor Agonists

INTERACTIONS WITH GLUCOCORTICOIDS AND ₂-AGONISTS^*

Mei Nie, Lisa Corbett, Alan J. Knox, and Linhua Pang

From the Division of Respiratory Medicine, City Hospital, University of Nottingham, Nottingham NG5 1PB, United Kingdom

Chemokine-mediated inflammatory cell infiltration is a hallmark of asthma. We recently demonstrated that glucocorticoids and ₂-agonists additively or synergistically suppress tumor necrosis factor- (TNF)-induced production of chemokines eotaxin and interleukin-8 (IL-8), respectively, in human airway smooth muscle (HASM) cells, which may partly explain their combined benefits in asthma. Peroxisome proliferator-activated receptors (PPARs) also modulate inflammatory gene expression. We reported here that the PPAR agonists 15-deoxy-^12,14-PGJ₂ (15d-PGJ₂) and troglitazone, but not PPAR agonist WY-14643, inhibited TNF-induced production of eotaxin and monocyte chemotactic protein-1 (MCP-1) but not IL-8. Eotaxin inhibition was transcriptional and additively enhanced by the glucocorticoid fluticasone and the ₂-agonist salmeterol, whereas MCP-1 inhibition was post-transcriptional and additively and synergistically enhanced by fluticasone and salmeterol, respectively. Coimmunoprecipitation revealed that 15d-PGJ₂ induced a protein-protein interaction between PPAR and the glucocorticoid receptor (GR) in TNF-treated HASM cells, which was enhanced by fluticasone and salmeterol. 15d-PGJ₂, fluticasone, and salmeterol all inhibited TNF-induced histone H4 acetylation at the eotaxin promoter and NF-B p65 binding to the eotaxin promoter and induced PPAR and GR association with the eotaxin promoter, as analyzed by chromatin immunoprecipitation assay. Our data suggest that chemokine expression in HASM cells is differentially regulated by PPAR agonists and that the interaction between PPAR and GR may be responsible for the additive and synergistic inhibition of chemokine expression by PPAR agonists, glucocorticoids, and ₂-agonists, particularly the chromatin-dependent suppression of eotaxin gene transcription. The interaction may have wide applications and may provide a potential target for pharmacological and molecular intervention.

Received for publication, September 15, 2004 , and in revised form, November 3, 2004.

^* This work was supported by Asthma UK Grant 01/029 and Glaxo-SmithKline. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence and reprint requests may be addressed: Division of Respiratory Medicine, Clinical Sciences Bldg., City Hospital, University of Nottingham, Hucknall Rd., Nottingham NG5 1PB, UK. Tel.: 44-115-8404779; Fax: 44-115-8404771; E-mail: mszmn1{at}gwmail.nottingham.ac.uk. To whom correspondence and reprint requests may be addressed. Tel.: 44-115-8404778; Fax: 44-115-8404771; E-mail: linhua.pang{at}nottingham.ac.uk.

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