title: PPARγ inhibits airway epithelial cell inflammatory response through a MUC1-dependent mechanism.
abstract: This study was conducted to examine the relationship between the peroxisome proliferator-associated receptor-γ (PPARγ) and MUC1 mucin, two anti-inflammatory molecules expressed in the airways. Treatment of A549 lung epithelial cells or primary mouse tracheal surface epithelial (MTSE) cells with phorbol 12-myristate 13-acetate (PMA) increased the levels of tumor necrosis factor (TNF)-α in cell culture media compared with cells treated with vehicle alone. Overexpression of MUC1 in A549 cells decreased PMA-stimulated TNF-α levels, whereas deficiency of Muc1 expression in MTSE cells from Muc1 null mice increased PMA-induced TNF-α levels. Treatment of A549 or MTSE cells with the PPARγ agonist troglitazone (TGN) blocked the ability of PMA to stimulate TNF-α levels. However, the effect of TGN required the presence of MUC1/Muc1, since no differences in TNF-α levels were seen between PMA and PMA plus TGN in MUC1/Muc1-deficient cells. Similarly, whereas TGN decreased interleukin-8 (IL-8) levels in culture media of MUC1-expressing A549 cells treated with Pseudomonas aeruginosa strain K (PAK), no differences in IL-8 levels were seen between PAK and PAK plus TGN in MUC1-nonexpressing cells. EMSA confirmed the presence of a PPARγ-binding element in the MUC1 gene promoter. Finally, TGN treatment of A549 cells increased MUC1 promoter activity measured using a MUC1-luciferase reporter gene, augmented MUC1 mRNA levels by quantitative RT-PCR, and enhanced MUC1 protein expression by Western blot analysis. These combined data are consistent with the hypothesis that PPARγ stimulates MUC1/Muc1 expression, thereby blocking PMA/PAK-induced TNF-α/IL-8 production by airway epithelial cells.
authors.affiliation: Center for Inflammation, Translational and Clinical Lung Research, Temple Univ. School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Yong Sung
authors.initials: YS
authors.lastname: Park
authors.forename: Erik P
authors.initials: EP
authors.lastname: Lillehoj
authors.forename: Kosuke
authors.initials: K
authors.lastname: Kato
authors.forename: Choon Sik
authors.initials: CS
authors.lastname: Park
authors.forename: Kwang Chul
authors.initials: KC
authors.lastname: Kim
mesh_terms: D000818:Animals; D002460:Cell Line; D002839:Chromans / Q000494:pharmacology; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018396:Mucin-1 / Q000235:genetics / Q000378:metabolism*; D009092:Mucous Membrane / Q000276:immunology / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011550:Pseudomonas aeruginosa / Q000472:pathogenicity; D012333:RNA, Messenger / Q000096:biosynthesis; D013755:Tetradecanoylphorbol Acetate / Q000378:metabolism / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology; D000077288:Troglitazone; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D002839:Chromans; D016209:Interleukin-8; D018396:Mucin-1; D047495:PPAR gamma; D012333:RNA, Messenger; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; D000077288:Troglitazone; D013755:Tetradecanoylphorbol Acetate