title: Differential regulation of chemokine expression by peroxisome proliferator-activated receptor gamma agonists: interactions with glucocorticoids and beta2-agonists.
abstract: Chemokine-mediated inflammatory cell infiltration is a hallmark of asthma. We recently demonstrated that glucocorticoids and beta(2)-agonists additively or synergistically suppress tumor necrosis factor-alpha (TNFalpha)-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 PPARgamma agonists 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)) and troglitazone, but not PPARalpha agonist WY-14643, inhibited TNFalpha-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 beta(2)-agonist salmeterol, whereas MCP-1 inhibition was post-transcriptional and additively and synergistically enhanced by fluticasone and salmeterol, respectively. Coimmunoprecipitation revealed that 15d-PGJ(2) induced a protein-protein interaction between PPARgamma and the glucocorticoid receptor (GR) in TNFalpha-treated HASM cells, which was enhanced by fluticasone and salmeterol. 15d-PGJ(2), fluticasone, and salmeterol all inhibited TNFalpha-induced histone H4 acetylation at the eotaxin promoter and NF-kappaB p65 binding to the eotaxin promoter and induced PPARgamma 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 PPARgamma agonists and that the interaction between PPARgamma and GR may be responsible for the additive and synergistic inhibition of chemokine expression by PPARgamma agonists, glucocorticoids, and beta(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.
authors.affiliation: Division of Respiratory Medicine, City Hospital, University of Nottingham, Nottingham NG5 1PB, United Kingdom. mszmn1@gwmail.nottingham.ac.uk
authors.forename: Mei
authors.initials: M
authors.lastname: Nie
authors.forename: Lisa
authors.initials: L
authors.lastname: Corbett
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Knox
authors.forename: Linhua
authors.initials: L
authors.lastname: Pang
mesh_terms: D000318:Adrenergic beta-Agonists / Q000378:metabolism; D000420:Albuterol / Q000031:analogs & derivatives* / Q000494:pharmacology; D000730:Androstadienes / Q000494:pharmacology; D015153:Blotting, Western; D002460:Cell Line; D054413:Chemokine CCL11; D018932:Chemokine CCL2 / Q000096:biosynthesis; D018925:Chemokines / Q000378:metabolism; D019742:Chemokines, CC / Q000096:biosynthesis / Q000378:metabolism; D002839:Chromans / Q000494:pharmacology; D002843:Chromatin / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D000068298:Fluticasone; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D016209:Interleukin-8 / Q000096:biosynthesis; D047493:PPAR alpha / Q000819:agonists; D047495:PPAR gamma / Q000819:agonists*; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D011485:Protein Binding; D011743:Pyrimidines / Q000494:pharmacology; D012313:RNA / Q000737:chemistry / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000068299:Salmeterol Xinafoate; D045162:Thiazolidinediones / Q000494:pharmacology; D014158:Transcription, Genetic; D014162:Transfection; D000077288:Troglitazone; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C097240:15-deoxy-delta(12,14)-prostaglandin J2; D000318:Adrenergic beta-Agonists; D000730:Androstadienes; C515456:CCL11 protein, human; D054413:Chemokine CCL11; D018932:Chemokine CCL2; D018925:Chemokines; D019742:Chemokines, CC; D002839:Chromans; D002843:Chromatin; D005938:Glucocorticoids; D016209:Interleukin-8; D047493:PPAR alpha; D047495:PPAR gamma; D011743:Pyrimidines; D011965:Receptors, Glucocorticoid; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; D012313:RNA; D000068299:Salmeterol Xinafoate; C006253:pirinixic acid; D000068298:Fluticasone; D000077288:Troglitazone; D000420:Albuterol; D015230:Prostaglandin D2