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

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Toll-Like Receptor 3 Signaling Induces Chronic Pancreatitis Through the Fas/Fas Ligand-Mediated Cytotoxicity Tohoku J. Exp. Med., 2009, 217, 175-184Fas/FasL-Mediated Cytotoxicity in Pancreatitis 175 Toll-Like Receptor 3 Signaling Induces Chronic Pancreatitis through the Fas/Fas Ligand-Mediated Cytotoxicity 1 1 1 1 YOSHIKO SOGA, HIROAKI KOMORI, TATSUHIKO MIYAZAKI, NORIMASA ARITA, 1 1 2 2 3 MIHO TERADA, KAZUO KAMADA, YUKI TANAKA, TAKAHIRO FUJINO, YOICHI HIASA, 3 3 1 BUNZO MATSUURA, MORIKAZU ONJI and MASATO NOSE 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. ──── poly I:C; MRL/lpr; MRL/gld; innate immunity; pancreatic duct epithelial cell. Tohoku J. Exp. Med., 2009, 217 (3), 175-184. © 2009 Tohoku University Medical Press Genetic and environmental factors are responsible for such as monocyte/macrophages and dendritic cells, fol- the development of autoimmune diseases. Environmental lowed by inducing immunomodulation, such as the activa- factors have a potential to induce loss of tolerance during tion of macrophages, NK and B cells and the production of central and peripheral differentiation of the adaptive cytokines and chemokines (Alexopoulou et al. 2001; immune response, followed by uncontrolled activation of Matsukura et al. 2006). In the previous study, poly I:C self-reactive B and T cells inducing autoimmunity and tis- injection to MRL/Mp mice generated chronic pancreatitis sue injury, which may be assisted by the cells of the innate (Qu et al. 2002). It has been shown that an RNA virus, immune system (Wen and Wong 2005). Toll-like receptors Coxackievirus B4, which is a prevalent human pathogen (TLRs) play important roles in innate immunity, thus lead- that is associated with pancreatits, autoimmune diabetes and ing to intracellular signaling to macrophages and dendritic myocarditis, induces TLR3 signaling (Richer et al. 2009). cells after the stimulation with various pathogens (Takeda Thus, TLR3 signaling contributes to the development of and Akira 2005). The inappropriate activation of TLR path- progressive inflammatory diseases. ways by these ligands may lead to the initiation and/or pro- In this study, we focused on analyzing the pathogenesis gression of autoimmune responses and tissue injury. of chronic pancreatitis induced by TLR3 signaling using an TLR3 recognizes viral double-stranded RNA (dsRNA) MRL/Mp mouse model. MRL/Mp mice spontaneously (Alexopoulou et al. 2001). Polyinosinic:polycytidylic acid develop chronic pancreatitis at an older age, possibly due to (poly I:C) is a synthetic dsRNA (Field et al. 1967) and rec- an autoimmune mechanism, since the pancreatitis was suc- ognized by TLR3 expressed on antigen-presenting cells cessfully transferred to younger mice by the injection of Received December 30, 2008; revision accepted for publication January 28, 2009. Correspondence: Masato Nose, MD, PhD, Department of Pathogenomics, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime 791-0295, Japan. e-mail: [email protected] 175 176 Y. Soga et al. Fas/FasL-Mediated Cytotoxicity in Pancreatitis 177 splenocytes from the older mice (Kanno et al. 1992), and gation and/or infiltration in the periductular regions without any poly I:C injection into younger MRL/Mp mice accelerates parenchymal destruction; grade 2+, focal parenchymal destruction the development of pancreatitis (Qu et al. 2002). Pancreatitis with mononuclear cell infiltration into ductular epithelium; grade 3+, in these mice is histopathologically characterized by the diffuse parenchymal destruction with granulomatous lesions and/or severe infiltration of lymphocytes, plasma cells and macro- the replacement of acinar tissues with fibrosis or adipose tissues (Fig. phages into the pancreatic parenchyma. Such lesions are 1). More than 10 lesions were examined in each individual. The average score was used as the pancreatitis index of each individual. thought to be initiated by the accumulation of lymphoid cells into the periductular regions and then the ductular epi- Immunohistochemistry thelial cells, followed by their destruction (Kanno et al. Paraffin-embedded tissues were used for identification of Fas. 1992; Qu et al. 2002), similar to autoimmune pancreatitis in After sectioning they were mounted of coated multi spot slides. human (Finkelberg et al. 2006; Zandieh and Byrne 2007). Immunohistochemical procedures were performed using the This initial event in the pancreas leads to the destruction of EnvisionTM Systems (Dako, Glostrup, Denmark) method, according to pancreatic acini, associated with the formation of granulo- the manufacturer’s instructions. Briefly, the sections were micro- matous lesions, with a partial regeneration of the ductules, waved for 10 min and washed with Tris-buffered saline (TBS). The thus showing so called “epithelial islands” (Okazaki et al. sections were incubated in PBS with 3% bovine serum albumin (BSA) 2008). Interestingly, the incidence of poly I:C-induced pan- to prevent nonspecific binding for 30 min. After washing twice in creatitis in MRL/Mp mice was higher than that in MRL/Mp TBS, the sections were incubated with rabbit anti-Fas (Wako, Osaka, mice bearing a Fas gene with the lpr mutation, MRL/Mp- Japan) for 1 overnight at 4°C followed by horseradish peroxidase lpr/lpr (Qu et al. 2002), which induces a deficit in Fas- labeled polymer-conjugated to goat anti-rabbit immunoglobulin for 1 mediated cytotoxicity (Watanabe-Fukunaga et al. 1992). hr. Antibody localization was effected using a peroxidase reaction The present study therefore demonstrates a critical role of with 3,3’-diaminobenzidine tetrahydrochloride (DAB) (Dako) as TLR3 signaling to generate the Fas/Fas ligand (FasL)- chromogen. The section was counterstained with hematoxylin. mediated cytotoxicity, leading to the development of pan- creatitis, associated with the effect of poly I:C directly act- Cell culture The pancreatic duct epithelial cell line MRL/S-1 was established ing on pancreatic epithelial cells. from the pancreas of an MRL/gld mouse to exclude the influence of functional FasL in subsequent studies. First, we prepared an MRL/gld MATERIALS AND METHODS mouse congenic with the SV40T-antigen transgene in the immortal- Mice ized strain of mice (Immortmice®) previously reported (Jat et al. lpr/lpr MRL/Mp-+/+ (MRL/+) and MRL/Mp- (MRL/lpr) mice 1991). In brief, an immortalized strain of mice was backcrossed for (Murphy and Roths 1978) were purchased from The Jackson MRL/gld more than 10 generations to establish MRL/Mp-gld/gld-TAg gld/gld Laboratory (Bar Harbor, ME, USA) and MRL/Mp- (MRL/gld) (MRL/gld-TAg). Thereafter, pancreatic tissue was prepared to per- mice which are deficit of functional FasL (Ito et al. 1997) were pur- form the culture in William’s E medium (Invitrogen, Carlsbad, CA, chased from Japan SLC, Inc. (Hamamatsu, Japan). They were main- USA) with 10% heat-inactivated fetal calf serum (FCS) (Invitrogen), tained in an animal center under specific pathogen-free conditions. supplemented with insulin (5 mg/l) (Sigma-Aldrich), IFNγ (200 The housing and care of the animals and all the procedures used in U/ml) (Biosource, Camarillo,CA, USA), penicillin (100 U/ml) (Banyu, these studies were performed in accordance with the guidelines and Tokyo, Japan), streptomycin (100 μg/ml) (Meiji, Tokyo, Japan) and regulations of the Ehime University Graduate School of Medicine. EGF (10 μg/l) (Sigma) at 33ºC. Mice were divided into two groups; poly I:C (5 mg/kg) (Sigma- MRL/S-1 cells were characterized using light microscopy, elec- n Aldrich, St. Louis, MO, USA) ( = 10, each of strains) or phosphate tron microscopy and immunocytochemistry. For electron microscopy, n bufferd saline (PBS) as control ( = 10, each of
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