Toll-like receptor 3 signaling induces chronic pancreatitis through the Fas/Fas ligand-mediated cytotoxicity

Yoshiko Soga, Hiroaki Komori, Tatsuhiko Miyazaki, Norimasa Arita, Miho Terada, Kazuo Kamada, Yuki Tanaka, Takahiro Fujino, Yoichi Hiasa, Bunzo Matsuura, Morikazu Onji, Masato Nose

Research output: Contribution to journalArticlepeer-review

20 Citations (Scopus)

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/ Ipr) 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/Ipr 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/Ipr 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.

Original languageEnglish
Pages (from-to)175-184
Number of pages10
JournalTohoku Journal of Experimental Medicine
Volume217
Issue number3
DOIs
Publication statusPublished - 2009

Keywords

  • Innate immunity
  • MRL/gld
  • MRL/lpr
  • Pancreatic duct epithelial cell
  • Poly I:C

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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