4.8 Article

The Cystic Fibrosis Transmembrane Conductance Regulator Controls Biliary Epithelial Inflammation and Permeability by Regulating Src Tyrosine Kinase Activity

期刊

HEPATOLOGY
卷 64, 期 6, 页码 2118-2134

出版社

WILEY-BLACKWELL
DOI: 10.1002/hep.28817

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资金

  1. National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health [RO1 DK096096, P30 DK034989, R01 NS069753, RO1DK101528]
  2. Fondazione Fibrosi Cistica [18-2012]
  3. Telethon [GGP12133]
  4. PSC Partners Seeking a Cure Foundation
  5. Jay and Deanie Stein CDA for Cancer Research, Mayo Clinic

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In the liver, the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) regulates bile secretion and other functions at the apical membrane of biliary epithelial cells (i.e., cholangiocytes). CF-related liver disease is a major cause of death in patients with CF. CFTR dysfunction affects innate immune pathways, generating a para-inflammatory status in the liver and other epithelia. This study investigates the mechanisms linking CFTR to toll-like receptor 4 activity. We found that CFTR is associated with a multiprotein complex at the apical membrane of normal mouse cholangiocytes, with proteins that negatively control Rous sarcoma oncogene cellular homolog (Src) activity. In CFTR-defective cholangiocytes, Src tyrosine kinase self-activates and phosphorylates toll-like receptor 4, resulting in activation of nuclear factor kappa-light-chain-enhancer of activated B cells and increased proinflammatory cytokine production in response to endotoxins. This Src/nuclear factor kappa-light-chain-enhancer of activated B cells-dependent inflammatory process attracts inflammatory cells but also generates changes in the apical junctional complex and loss of epithelial barrier function. Inhibition of Src decreased the inflammatory response of CF cholangiocytes to lipopolysaccharide, rescued the junctional defect in vitro, and significantly attenuated endotoxin-induced biliary damage and inflammation in vivo (Cftr knockout mice). Conclusion: These findings reveal a novel function of CFTR as a regulator of toll-like receptor 4 responses and cell polarity in biliary epithelial cells; this mechanism is pathogenetic, as shown by the protective effects of Src inhibition in vivo, and may be a novel therapeutic target in CF-related liver disease and other inflammatory cholangiopathies.

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