title: Toll-like receptor 3 signaling induces chronic pancreatitis through the Fas/Fas ligand-mediated cytotoxicity.
abstract: Innate immunity plays important roles in host defense against pathogens, but may also contribute to the development of autoimmune diseases under certain conditions. Toll-like receptors (TLRs) recognize various pathogens and induce innate immunity. We herein present a mouse model for chronic pancreatitis, which was induced by TLR3 signaling that generated the Fas/Fas ligand (FasL)-mediated cytotoxicity. An analogue of viral double-stranded RNA, polyinosinic:polycytidylic acid (poly I:C), which is recognized by TLR3, was injected into autoimmune-prone strains: MRL/Mp mice (MRL/+), MRL/Mp mice with a deficit of Fas (MRL/lpr) and MRL/Mp mice with a deficit of functional FasL (MRL/gld). The pancreatitis in MRL/+ mice was initiated by the destruction of pancreatic ductules, and its severity was significantly higher than that in MRL/lpr mice or MRL/gld mice. Using a pancreatic duct epithelial cell line MRL/S-1 newly established from the MRL/gld mouse that lacks FasL, we showed that treatment with poly I:C significantly induced the expression of Fas on the cultured cells. MRL/S-1 cells were destructed when co-cultured with splenocytes bearing intact FasL prepared from MRL/+ or MRL/lpr mice, but the magnitude of cytotoxicity was smaller with splenocytes of MRL/gld mice. Likewise, synthetic FasL protein showed cytotoxicity on MRL/S-1 cells. Furthermore, MRL/S-1 cells expressed higher levels of chemokines after the treatment with poly I:C, suggesting that the poly I:C-mediated induction of chemokines may be responsible for recruitment of lymphoid cells to the pancreatic periductular regions. These findings indicate that TLR3 signaling generates the Fas/FasL-mediated cytotoxicity, thereby leading to the development of chronic pancreatitis.
authors.affiliation: Department of Pathogenomics, Ehime University Graduate School of Medicine, Ehime, Japan.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Soga
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Komori
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Miyazaki
authors.forename: Norimasa
authors.initials: N
authors.lastname: Arita
authors.forename: Miho
authors.initials: M
authors.lastname: Terada
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kamada
authors.forename: Yuki
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Takahiro
authors.initials: T
authors.lastname: Fujino
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Hiasa
authors.forename: Bunzo
authors.initials: B
authors.lastname: Matsuura
authors.forename: Morikazu
authors.initials: M
authors.lastname: Onji
authors.forename: Masato
authors.initials: M
authors.lastname: Nose
mesh_terms: D000818:Animals; D002460:Cell Line; D018925:Chemokines / Q000378:metabolism; D003601:Cytotoxicity Tests, Immunologic; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D004847:Epithelial Cells; D053222:Fas Ligand Protein / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D007113:Immunity, Innate; D007150:Immunohistochemistry; D051379:Mice; D008817:Mice, Mutant Strains; D046228:Microarray Analysis; D050500:Pancreatitis, Chronic / Q000209:etiology* / Q000276:immunology; D011070:Poly I-C / Q000378:metabolism / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D051196:Toll-Like Receptor 3 / Q000378:metabolism*
chemical_list: D018925:Chemokines; D053222:Fas Ligand Protein; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D011070:Poly I-C