Stimulation of nuclear receptor peroxisome proliferator-activated receptor-? limits NF-?B-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-?B)-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-? (PPAR-?), may counterregulate inflammation in a tissue-specific manner. In this study, we explored the anti-inflammatory effect of PPAR-? 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-? 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-? (pioglitazone and rosiglitazone) up-regulates PPAR-?-dependent genes, while inhibiting the activation of NF-?B 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-? agonists modulate NF-?B-dependent inflammation by up-regulating nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor alpha, a negative regulator of NF-?B. Stimulation of PPAR-? in vivo (rosiglitazone) significantly attenuates biliary damage and inflammation in Cftr-knockout mice exposed to a dextran sodium sulfate-induced portal endotoxemia.These studies unravel a novel function of PPAR-? in controlling biliary epithelium inflammation and suggest that impaired activation of PPAR-? contributes to the chronic inflammatory state of CFTR-defective cholangiocytes.

SUBMITTER: Scirpo R 

PROVIDER: S-EPMC4618241 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature