Toll-Like Receptor 3 Signaling Induces Chronic Pancreatitis through the Fas/Fas Ligand-Mediated Cytotoxicity

DOI Web Site PubMed 被引用文献9件 参考文献52件
  • Soga Yoshiko
    Department of Pathogenomics, Ehime University Graduate School of Medicine
  • Komori Hiroaki
    Department of Pathogenomics, Ehime University Graduate School of Medicine
  • Miyazaki Tatsuhiko
    Department of Pathogenomics, Ehime University Graduate School of Medicine
  • Arita Norimasa
    Department of Pathogenomics, Ehime University Graduate School of Medicine
  • Terada Miho
    Department of Pathogenomics, Ehime University Graduate School of Medicine
  • Kamada Kazuo
    Department of Pathogenomics, Ehime University Graduate School of Medicine
  • Tanaka Yuki
    Integrated Center for Sciences, Ehime University
  • Fujino Takahiro
    Integrated Center for Sciences, Ehime University
  • Hiasa Yoichi
    Department of Gastroenteology and Metabology, Ehime University Graduate School of Medicine
  • Matsuura Bunzo
    Department of Gastroenteology and Metabology, Ehime University Graduate School of Medicine
  • Onji Morikazu
    Department of Gastroenteology and Metabology, Ehime University Graduate School of Medicine
  • Nose Masato
    Department of Pathogenomics, Ehime University Graduate School of Medicine

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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.

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