Peroxisome proliferator-activated receptor-gamma 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-kappaB activation. Peroxisome proliferator-activated receptor-gamma (PPARgamma) inhibits NF-kappaB activity and is reported to be reduced in CF. If PPARgamma participates in regulatory dysfunction in the CF lung, perhaps PPARgamma ligands might be useful therapeutically. Cell models of CF airway epithelium were used to evaluate PPARgamma expression and binding to NF-kappaB at basal and under conditions of inflammatory stimulation by Pseudomonas aeruginosa or TNFalpha/IL-1beta. An animal model of CF was used to evaluate the potential of PPARgamma agonists as therapeutic agents in vivo. In vitro, PPARgamma agonists reduced IL-8 and MMP-9 release from airway epithelial cells in response to PAO1 or TNFalpha/IL-1beta stimulation. Less NF-kappaB bound to PPARgamma in CF than normal cells, in two different assays; PPARgamma agonists abrogated this reduction. PPARgamma bound less to its target DNA sequence in CF cells. To test the importance of the reported PPARgamma inactivation by phosphorylation, we observed that inhibitors of ERK, but not JNK, were synergistic with PPARgamma agonists in reducing IL-8 secretion. In vivo, administration of PPARgamma agonists reduced airway inflammation in response to acute infection with P. aeruginosa in CF, but not wild-type, mice. In summary, PPARgamma inhibits the inflammatory response in CF, at least in part by interaction with NF-kappaB in airway epithelial cells. PPARgamma agonists may be therapeutic in CF.
Deptartment of Pediatrics, School of Medicine, Case Western Reserve University, BRB Bldg. R829, 10900 Euclid Ave., Cleveland, OH 44106-4948, USA. aura.perez@case.edu
Aura
A
Perez
Anna M
AM
van Heeckeren
David
D
Nichols
Sanhita
S
Gupta
Jean F
JF
Eastman
Pamela B
PB
Davis
D000818:Animals; D003550:Cystic Fibrosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011552:Pseudomonas Infections / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011550:Pseudomonas aeruginosa; D020545:Respiratory Mucosa / Q000378:metabolism* / Q000473:pathology
D016207:Cytokines; D018836:Inflammation Mediators; D016328:NF-kappa B; D047495:PPAR gamma; D047428:Protein Kinase Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases; D048670:MAP Kinase Kinase 4; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse