Peroxisome proliferator-activated receptor-γ in cystic fibrosis lung epithelium

The pathophysiology of cystic fibrosis (CF) inflammatory lung disease is not well understood. CF airway epithelial cells respond to inflammatory stimuli with increased production of proinflammatory cytokines as a result of increased NF-kappa B activation. Peroxisome proliferator-activated receptor-gamma (PPAR gamma) inhibits NF-kappa B activity and is reported to be reduced in CF. If PPAR gamma participates in regulatory dysfunction in the CF lung, perhaps PPAR gamma ligands might be useful therapeutically. Cell models of CF airway epithelium were used to evaluate PPAR gamma expression and binding to NF-kappa B at basal and under conditions of inflammatory stimulation by Pseudomonas aeruginosa or TNF alpha/IL-1 beta. An animal model of CF was used to evaluate the potential of PPAR gamma agonists as therapeutic agents in vivo. In vitro, PPAR gamma agonists reduced IL-8 and MMP-9 release from airway epithelial cells in response to PAO1 or TNF alpha/ IL-1 beta stimulation. Less NF-kappa B bound to PPAR gamma in CF than normal cells, in two different assays; PPAR gamma agonists abrogated this reduction. PPAR gamma bound less to its target DNA sequence in CF cells. To test the importance of the reported PPAR gamma inactivation by phosphorylation, we observed that inhibitors of ERK, but not JNK, were synergistic with PPAR gamma agonists in reducing IL-8 secretion. In vivo, administration of PPAR gamma agonists reduced airway inflammation in response to acute infection with P. aeruginosa in CF, but not wildtype, mice. In summary, PPAR gamma inhibits the inflammatory response in CF, at least in part by interaction with NF-kappa B in airway epithelial cells. PPAR gamma agonists may be therapeutic in CF.