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Innate immune response to double‐stranded RNA in biliary epithelial cells is associated with the pathogenesis of biliary atresia
Author(s) -
Harada Kenichi,
Sato Yasunori,
Itatsu Keita,
Isse Kumiko,
Ikeda Hiroko,
Yasoshima Mitsue,
Zen Yoh,
Matsui Akira,
Nakanuma Yasuni
Publication year - 2007
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.21797
Subject(s) - biology , tlr3 , interferon , innate immune system , mda5 , protein kinase r , rna silencing , interferon regulatory factors , microbiology and biotechnology , rotavirus , tumor necrosis factor alpha , apoptosis , cancer research , immune system , signal transduction , virology , rna , immunology , toll like receptor , gene , virus , rna interference , protein kinase c , biochemistry , mitogen activated protein kinase kinase
Infections of Reoviridae consisting of a double‐stranded RNA (dsRNA) genome are a possible cause of biliary atresia (BA). The aim of the present study is to clarify the pathophysiological function of dsRNA viruses in the pathogenesis of BA. The expression of dsRNA pattern‐recognizing receptors, Toll‐like receptor 3 (TLR3), retinoic acid inducible gene I (RIG‐I), melanoma differentiation‐associated gene‐5 (MDA‐5), and dsRNA‐activated protein kinase R (PKR) was constitutively detected in cultured human biliary epithelial cells (BECs). Stimulation with polyinosinic‐polycytidylic acid [poly(I:C), a synthetic analog of viral dsRNA] induced the activation of transcription factors [nuclear factor (NF)‐κB and interferon regulatory factor 3 (IRF3)] and the production of interferon‐β1 (IFN‐β1) and MxA as potent antiviral responses. Moreover, poly(I:C) up‐regulated the expression of tumor necrosis factor–related apoptosis‐inducing ligand (TRAIL), and both poly(I:C) and TRAIL reduced the viability of cultured human BECs by enhancing apoptosis. Experiments in vivo using tissue sections of extrahepatic bile ducts from patients with BA and controls (choledochal cysts and nonbiliary diseases) showed that the activation of NF‐κB, interferon regulatory factor‐3 (IRF‐3), and PKR, and the enhancement of TRAIL and single‐stranded DNA (ssDNA)–positive apoptosis were significant in BA, although extrahepatic bile ducts diffusely and constantly expressed TLR3 in all diseases. Conclusion : dsRNA viruses could directly induce the expression of TRAIL and apoptosis in human biliary epithelial cells as a result of the biliary innate immune response, supporting the notion that Reoviridae infections are directly associated with the pathogenesis of cholangiopathies in cases of BA. (H EPATOLOGY 2007.)