BACKGROUND/AIMS: 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.
BACKGROUND/AIMS: 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.
Authors: Alessia Omenetti; Lee M Bass; Robert A Anders; Maria G Clemente; Heather Francis; Cynthia D Guy; Shannon McCall; Steve S Choi; Gianfranco Alpini; Kathleen B Schwarz; Anna Mae Diehl; Peter F Whitington Journal: Hepatology Date: 2011-04 Impact factor: 17.425
Authors: Jacqueline Neagos; Theodore J Standiford; Michael W Newstead; Xianying Zeng; Steven K Huang; Megan N Ballinger Journal: Am J Respir Cell Mol Biol Date: 2015-12 Impact factor: 6.914