title: Intermedilysin induces EGR-1 expression through calcineurin/NFAT pathway in human cholangiocellular carcinoma cells.
abstract: Intermedilysin (ILY) is a cholesterol-dependent cytolysin produced by Streptococcus intermedius, which is associated with human brain and liver abscesses. Although intrahepatic bile duct cells play a valuable role in the pathogenesis of liver abscess, the molecular mechanism of ILY-treated intrahepatic bile duct cells remains unknown. In this study, we report that ILY induced a nuclear accumulation of intracellular calcium ([Ca(2+)]i) in human cholangiocellular cells HuCCT1. We also demonstrate that 10 ng/ml ILY induced NFAT1 dephosphorylation and its nuclear translocation in HuCCT1 cells. In contrast to the result that ILY induced NF-κB translocation in human hepatic HepG2 cells, ILY did not affect NF-κB localization in HuCCT1 cells. Dephosphorylation and nuclear translocation of NFAT1 caused by ILY were prevented by [Ca(2+)]i calcium chelator, BAPTA/AM, and calcineurin inhibitors, cyclosporine A and tacrolimus. ILY induced early growth response-1 (EGR-1) expression and it was inhibited by the pre-treatment with cyclosporine A, indicating that the calcineurin/NFAT pathway was involved in EGR-1 expression in response to ILY. ILY-induced calcineurin/NFAT1 activation and sequential EGR-1 expression might be related to the pathogenesis of S. intermedius in human bile duct cells.
authors.affiliation: Department of Oral Microbiology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8504, Japan.
authors.forename: Heni
authors.initials: H
authors.lastname: Susilowati
authors.forename: Hirohiko
authors.initials: H
authors.lastname: Okamura
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Hirota
authors.forename: Masayuki
authors.initials: M
authors.lastname: Shono
authors.forename: Kaya
authors.initials: K
authors.lastname: Yoshida
authors.forename: Keiji
authors.initials: K
authors.lastname: Murakami
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tabata
authors.forename: Hideaki
authors.initials: H
authors.lastname: Nagamune
authors.forename: Tatsuji
authors.initials: T
authors.lastname: Haneji
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Miyake
mesh_terms: D001430:Bacteriocins / Q000378:metabolism* / Q000494:pharmacology; D001653:Bile Ducts, Intrahepatic / Q000187:drug effects / Q000378:metabolism*; D019703:Calcineurin / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D051766:Early Growth Response Protein 1 / Q000096:biosynthesis*; D006801:Humans; D050778:NFATC Transcription Factors / Q000378:metabolism*
chemical_list: D001430:Bacteriocins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D050778:NFATC Transcription Factors; C494006:NFATC2 protein, human; C403910:intermedilysin protein, Streptococcus intermedius; D019703:Calcineurin; D002118:Calcium