PPAR?? inhibits airway epithelial cell inflammatory response through a MUC1-dependent mechanism

摘要

This study was conducted to examine the relationship between the peroxisome proliferator-associated receptor-?? (PPAR??) 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)-?? in cell culture media compared with cells treated with vehicle alone. Overexpression of MUC1 in A549 cells decreased PMA-stimulated TNF-?? levels, whereas deficiency of Muc1 expression in MTSE cells from Muc1 null mice increased PMA-induced TNF-?? levels. Treatment of A549 or MTSE cells with the PPAR?? agonist troglitazone (TGN) blocked the ability of PMA to stimulate TNF-?? levels. However, the effect of TGN required the presence of MUC1/Muc1, since no differences in TNF-?? 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 PPAR??-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 PPAR?? stimulates MUC1/Muc1 expression, thereby blocking PMA/PAK-induced TNF-??/IL-8 production by airway epithelial cells. ? 2012 the American Physiological Society.