title: Stimulation of nuclear receptor peroxisome proliferator-activated receptor-γ limits NF-κB-dependent inflammation in mouse cystic fibrosis biliary epithelium.
abstract: 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-κB)-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-γ (PPAR-γ), may counterregulate inflammation in a tissue-specific manner. In this study, we explored the anti-inflammatory effect of PPAR-γ 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-γ 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-γ (pioglitazone and rosiglitazone) up-regulates PPAR-γ-dependent genes, while inhibiting the activation of NF-κB 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-γ agonists modulate NF-κB-dependent inflammation by up-regulating nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor alpha, a negative regulator of NF-κB. Stimulation of PPAR-γ in vivo (rosiglitazone) significantly attenuates biliary damage and inflammation in Cftr-knockout mice exposed to a dextran sodium sulfate-induced portal endotoxemia.
  
  
  CONCLUSIONS
  These studies unravel a novel function of PPAR-γ in controlling biliary epithelium inflammation and suggest that impaired activation of PPAR-γ contributes to the chronic inflammatory state of CFTR-defective cholangiocytes.
authors.affiliation: Section of Digestive Diseases, Liver Center, Yale University, New Haven, CT.|Department of Surgery and Translational Medicine, University of Milano-Bicocca, Milan, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Scirpo
authors.affiliation: Section of Digestive Diseases, Liver Center, Yale University, New Haven, CT.
authors.forename: Romina
authors.initials: R
authors.lastname: Fiorotto
authors.affiliation: Section of Digestive Diseases, Liver Center, Yale University, New Haven, CT.
authors.forename: Ambra
authors.initials: A
authors.lastname: Villani
authors.affiliation: Section of Digestive Diseases, Liver Center, Yale University, New Haven, CT.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Amenduni
authors.affiliation: Section of Digestive Diseases, Liver Center, Yale University, New Haven, CT.
authors.forename: Carlo
authors.initials: C
authors.lastname: Spirli
authors.affiliation: Section of Digestive Diseases, Liver Center, Yale University, New Haven, CT.|Department of Surgery and Translational Medicine, University of Milano-Bicocca, Milan, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Strazzabosco
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002761:Cholangitis / Q000209:etiology*; D003550:Cystic Fibrosis / Q000473:pathology*; D016207:Cytokines / Q000096:biosynthesis; D004848:Epithelium / Q000378:metabolism; D020672:I-kappa B Proteins / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018181:Mice, Inbred CFTR; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000502:physiology*; D047495:PPAR gamma / Q000819:agonists / Q000502:physiology*
chemical_list: D016207:Cytokines; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D047495:PPAR gamma; D000072000:NF-KappaB Inhibitor alpha