| First Author | Scirpo R | Year | 2015 |
| Journal | Hepatology | Volume | 62 |
| Issue | 5 | Pages | 1551-62 |
| PubMed ID | 26199136 | Mgi Jnum | J:323268 |
| Mgi Id | MGI:6880515 | Doi | 10.1002/hep.28000 |
| Citation | Scirpo R, et al. (2015) Stimulation of nuclear receptor peroxisome proliferator-activated receptor-gamma limits NF-kappaB-dependent inflammation in mouse cystic fibrosis biliary epithelium. Hepatology 62(5):1551-62 |
| abstractText | UNLABELLED: Cystic fibrosis-associated liver disease is a chronic cholangiopathy that negatively affects the quality of life of cystic fibrosis patients. In addition to reducing biliary chloride and bicarbonate secretion, up-regulation of toll-like receptor 4/nuclear factor kappa light-chain-enhancer of activated B cells (NF-kappaB)-dependent immune mechanisms plays a major role in the pathogenesis of cystic fibrosis-associated liver disease and may represent a therapeutic target. Nuclear receptors are transcription factors that regulate several intracellular functions. Some nuclear receptors, including peroxisome proliferator-activated receptor-gamma (PPAR-gamma), may counterregulate inflammation in a tissue-specific manner. In this study, we explored the anti-inflammatory effect of PPAR-gamma stimulation in vivo in cystic fibrosis transmembrane conductance regulator (Cftr) knockout mice exposed to dextran sodium sulfate and in vitro in primary cholangiocytes isolated from wild-type and from Cftr-knockout mice exposed to lipopolysaccharide. We found that in CFTR-defective biliary epithelium expression of PPAR-gamma is increased but that this does not result in increased receptor activity because the availability of bioactive ligands is reduced. Exogenous administration of synthetic agonists of PPAR-gamma (pioglitazone and rosiglitazone) up-regulates PPAR-gamma-dependent genes, while inhibiting the activation of NF-kappaB and the secretion of proinflammatory cytokines (lipopolysaccharide-induced CXC chemokine, monocyte chemotactic protein-1, macrophage inflammatory protein-2, granulocyte colony-stimulating factor, keratinocyte chemoattractant) in response to lipopolysaccharide. PPAR-gamma agonists modulate NF-kappaB-dependent inflammation by up-regulating nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor alpha, a negative regulator of NF-kappaB. Stimulation of PPAR-gamma in vivo (rosiglitazone) significantly attenuates biliary damage and inflammation in Cftr-knockout mice exposed to a dextran sodium sulfate-induced portal endotoxemia. CONCLUSION: These studies unravel a novel function of PPAR-gamma in controlling biliary epithelium inflammation and suggest that impaired activation of PPAR-gamma contributes to the chronic inflammatory state of CFTR-defective cholangiocytes. |
