Induction of innate immune response and absence of subsequent tolerance to dsRNA in biliary epithelial cells relate to the pathogenesis of biliary atresia.
OBJECTIVE
Biliary epithelial cells (BECs) possess negative regulatory mechanisms of Toll-like receptor (TLR)-based tolerance to bacteria (e.g. endotoxin tolerance). Viral infections of the Reoviridae genus with a dsRNA genome are suspected to be part of the aetiology of biliary atresia (BA), but the negative biliary mechanisms remain unexplored.


METHODS
Cultured human intrahepatic BECs (HIBECs) pretreated with polyinosinic-polycytidylic acid [poly(I:C)] (a synthetic analogue of viral dsRNA) for 24 h were exposed to poly(I:C) in fresh medium. The activation of nuclear factor-kappaB (NF-kappaB) and the expression of myxovirus resistance protein A (MxA) and tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) mRNAs were evaluated. Moreover, after the pretreatment, the transition of these molecules was examined in poly(I:C)-free conditions.


RESULTS
Treatment with poly(I:C) significantly upregulated NF-kappaB activity in fresh HIBECs, and pretreatment failed to show tolerance to poly(I:C). The production of MxA and TRAIL was also preserved. Moreover, upregulation in the pretreated HIBECs was well preserved in poly(I:C)-free medium for at least 72 h.


CONCLUSIONS
BECs fail to show tolerance to poly(I:C), and once innate immunity is activated it is sustained in poly(I:C)-free conditions, suggesting that the initiation of the immune response to dsRNA in HIBECs and its presence after the clearance of virus are closely associated with the progression of BA.
Harada
Kenichi
K
Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
Sato
Yasunori
Y
Isse
Kumiko
K
Ikeda
Hiroko
H
Nakanuma
Yasuni
Y
D001653:Bile Ducts, Intrahepatic / Q000166:cytology / Q000276:immunology*; D001656:Biliary Atresia / Q000276:immunology* / Q000821:virology; D002460:Cell Line; D004847:Epithelial Cells / Q000276:immunology; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance; D007113:Immunity, Innate; D064547:Myxovirus Resistance Proteins; D011070:Poly I-C; D012330:RNA, Double-Stranded / Q000276:immunology*; D012367:RNA, Viral / Q000276:immunology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism
C579071:MX1 protein, human; D064547:Myxovirus Resistance Proteins; D012330:RNA, Double-Stranded; D012367:RNA, Viral; D053221:TNF-Related Apoptosis-Inducing Ligand; D019204:GTP-Binding Proteins; D011070:Poly I-C