Innate immune response to double-stranded RNA in biliary epithelial cells is associated with the pathogenesis of biliary atresia.
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)-kappaB and interferon regulatory factor 3 (IRF3)] and the production of interferon-beta1 (IFN-beta1) 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-kappaB, 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.


CONCLUSIONS
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.
Harada
Kenichi
K
Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
Sato
Yasunori
Y
Itatsu
Keita
K
Isse
Kumiko
K
Ikeda
Hiroko
H
Yasoshima
Mitsue
M
Zen
Yoh
Y
Matsui
Akira
A
Nakanuma
Yasuni
Y
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001652:Bile Ducts / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D001656:Biliary Atresia / Q000378:metabolism / Q000503:physiopathology / Q000821:virology*; D002478:Cells, Cultured; D002675:Child, Preschool; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D004847:Epithelial Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects / Q000502:physiology*; D007223:Infant; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D000072640:Interferon-Induced Helicase, IFIH1; D016899:Interferon-beta / Q000378:metabolism; D008297:Male; D064547:Myxovirus Resistance Proteins; D016328:NF-kappa B / Q000378:metabolism; D011070:Poly I-C / Q000494:pharmacology; D012330:RNA, Double-Stranded / Q000235:genetics / Q000502:physiology*; D011971:Receptors, Immunologic; D012087:Reoviridae / Q000235:genetics / Q000472:pathogenicity*; D012088:Reoviridae Infections / Q000150:complications / Q000276:immunology / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D051196:Toll-Like Receptor 3 / Q000378:metabolism
D050838:Interferon Regulatory Factor-3; C579071:MX1 protein, human; D064547:Myxovirus Resistance Proteins; D016328:NF-kappa B; D012330:RNA, Double-Stranded; D011971:Receptors, Immunologic; C495344:TLR3 protein, human; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D051196:Toll-Like Receptor 3; D016899:Interferon-beta; C452820:RIGI protein, human; D019204:GTP-Binding Proteins; C452815:IFIH1 protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1; D011070:Poly I-C