title: Interaction of Toll-like receptors with bacterial components induces expression of CDX2 and MUC2 in rat biliary epithelium in vivo and in culture.
abstract: The mechanism of transformation of biliary epithelium leading to intestinal metaplasia, which is significantly involved in biliary diseases, remains unclear. CDX2, an intestine-specific transcription factor, is thought to regulate intestinal mucin MUC2 (mucus core protein) expression. We took advantage of polycystic kidney (PCK) rats as a model of chronic suppurative cholangitis with intestinal metaplasia and of cultured biliary epithelial cells (BECs) from PCK rats to clarify the causal relation between bacterial components such as pathogen-associated molecular patterns (PAMPs) and the development of intestinal metaplasia of bile ducts. Histological, immunohistochemical, and in situ hybridization studies were conducted in PCK rat livers. In cultured BECs, CDX2 and MUC2 were expressed following treatment with PAMPs and inhibitors (anti-Toll-like receptor (TLR)2/TLR4 antibody, nuclear factor-kappaB (NF-kappaB) inhibitor MG132). Chronic suppurative cholangitis with intestinal metaplasia developed as the PCK rats aged, and intestinal metaplasia and aberrant CDX2 and MUC2 expression developed in parallel. Intraluminal bacteria and the expression of TLR2 and TLR4 in BECs were demonstrated in the bile ducts, showing chronic suppurative cholangitis. In cultured BECs, treatment with PAMPs induced upregulation of CDX2 and MUC2 expression, and this effect was abolished by pretreatment with anti-TLR2 and anti-TLR4 antibody and MG132. A knockdown of CDX2 by CDX2 small interfering RNA inhibited MUC2 expression in cultured BECs induced by PAMPs, and transfection of CDX2 expression vector induced MUC2 expression. In conclusion, bacterial components may induce upregulation of the CDX2 expression followed by MUC2 expression via TLR and the NF-kappaB system in cultured BECs, and could be related to the development of intestinal metaplasia of the bile ducts.
authors.affiliation: Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Ikeda
authors.forename: Motoko
authors.initials: M
authors.lastname: Sasaki
authors.forename: Akira
authors.initials: A
authors.lastname: Ishikawa
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Sato
authors.forename: Kenichi
authors.initials: K
authors.lastname: Harada
authors.forename: Yoh
authors.initials: Y
authors.lastname: Zen
authors.forename: Hideaki
authors.initials: H
authors.lastname: Kazumori
authors.forename: Yasuni
authors.initials: Y
authors.lastname: Nakanuma
mesh_terms: D000375:Aging; D000818:Animals; D001426:Bacterial Proteins / Q000494:pharmacology*; D001653:Bile Ducts, Intrahepatic / Q000166:cytology* / Q000382:microbiology; D000071616:CDX2 Transcription Factor; D016767:Caroli Disease / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects*; D019084:Fluorescent Antibody Technique, Indirect; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D066298:In Vitro Techniques; D007976:Leupeptins / Q000494:pharmacology; D008297:Male; D008679:Metaplasia / Q000378:metabolism / Q000473:pathology; D055262:Mucin-2; D009077:Mucins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D051195:Toll-Like Receptor 2 / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000276:immunology*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D000071616:CDX2 Transcription Factor; D015853:Cysteine Proteinase Inhibitors; D018398:Homeodomain Proteins; D007976:Leupeptins; C524628:Muc2 protein, rat; D055262:Mucin-2; D009077:Mucins; D012333:RNA, Messenger; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D015534:Trans-Activators; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde