Stimulation of nuclear receptor peroxisome proliferator-activated receptor-γ limits NF-κB-dependent inflammation in mouse cystic fibrosis biliary epithelium.

Abstract

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-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.

CONCLUSION:

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: Roberto Scirpo, Romina Fiorotto, Ambra Villani, Mariangela Amenduni, Carlo Spirli, Mario Strazzabosco
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 62 Issue 5 Pg. 1551-62 (Nov 2015) ISSN: 1527-3350 [Electronic] United States
• PMID: 26199136 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by the American Association for the Study of Liver Diseases.

Chemical References

• Cytokines
• I-kappa B Proteins
• Lipopolysaccharides
• NF-kappa B
• Nfkbia protein, mouse
• PPAR gamma
• NF-KappaB Inhibitor alpha

Topics

• Animals
• Cells, Cultured
• Cholangitis (etiology)
• Cystic Fibrosis (pathology)
• Cytokines (biosynthesis)
• Epithelium (metabolism)
• I-kappa B Proteins (physiology)
• Lipopolysaccharides (pharmacology)
• Mice
• Mice, Inbred C57BL
• Mice, Inbred CFTR
• NF-KappaB Inhibitor alpha
• NF-kappa B (physiology)
• PPAR gamma (agonists, physiology)