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

Abstract

Park YS, Lillehoj EP, Kato K, Park CS, Kim KC. PPAR gamma inhibits airway epithelial cell inflammatory response through a MUC1-dependent mechanism. Am J Physiol Lung Cell Mol Physiol 302: L679-L687, 2012. First published January 20, 2012; doi: 10.1152/ajplung.00360.2011.-This study was conducted to examine the relationship between the peroxisome proliferator-associated receptor-gamma (PPAR gamma) 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)-alpha in cell culture media compared with cells treated with vehicle alone. Over-expression of MUC1 in A549 cells decreased PMA-stimulated TNF-alpha levels, whereas deficiency of Muc1 expression in MTSE cells from Muc1 null mice increased PMA-induced TNF-alpha levels. Treatment of A549 or MTSE cells with the PPAR gamma agonist troglitazone (TGN) blocked the ability of PMA to stimulate TNF-alpha levels. However, the effect of TGN required the presence of MUC1/Muc1, since no differences in TNF-alpha 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 gamma-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 gamma stimulates MUC1/Muc1 expression, thereby blocking PMA/PAK-induced TNF-alpha/IL-8 production by airway epithelial cells.