Tohoku J. Exp. Med., 2009, 217(3)

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

YOSHIKO SOGA,¹ HIROAKI KOMORI,¹ TATSUHIKO MIYAZAKI,¹ NORIMASA ARITA,¹ MIHO TERADA,¹ KAZUO KAMADA,¹ YUKI TANAKA,² TAKAHIRO FUJINO,² YOICHI HIASA,³ BUNZO MATSUURA,³ MORIKAZU ONJI³ and MASATO NOSE¹

¹Department of Pathogenomics, Ehime University Graduate School of Medicine, Ehime, Japan
²Integrated Center for Sciences, Ehime University, Ehime, Japan
³Department of Gastroenteology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan

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.

keywords —— poly I:C; MRL/lpr; MRL/gld; innate immunity; pancreatic duct epithelial cell.

© 2009 Tohoku University Medical Press

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Tohoku J. Exp. Med., 2009, 217, 175-184

Correspondence: Masato Nose, MD, PhD, Department of Pathogenomics, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime 791-0295, Japan.

e-mail: masanose@m.ehime-u.ac.jp