Masahiro Takeo1, Akiyoshi Nishio2, Masataka Masuda1, Kazunori Aoi3, Takashi Okazaki3, Toshiro Fukui1, Kazushige Uchida4, Makoto Naganuma1, Kazuichi Okazaki1. 1. Department of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, Japan. 2. Department of Gastroenterology and Hepatology, Kansai Medical University Medical Center, 10-15 Fumizono-cho, Moriguchi, Osaka, 570-8507, Japan. nishioa@takii.kmu.ac.jp. 3. Department of Gastroenterology and Hepatology, Kansai Medical University Medical Center, 10-15 Fumizono-cho, Moriguchi, Osaka, 570-8507, Japan. 4. Department of Gastroenterology and Hepatology, Kochi Medical School, 185-1 Kohasu Okocho, Nankoku, Kochi, Japan.
Abstract
BACKGROUND: Stimulation of Toll-like receptor 3 (TLR3) induces autoimmune-mediated pancreatitis in susceptible mice, whereas stimulation of TLR4 causes nonautoimmune-mediated pancreatitis. However, the effects of TLR2 stimulation on the pancreas are unknown. AIMS: We investigated the role of TLR2 stimulation on pancreatic damage by repeatedly stimulating mice with TLR2 ligands. METHODS: Wild-type (WT) and interleukin 10-deficient (IL-10-knockout (KO)) mice were administered zymosan and lipoteichoic acid (LTA) intraperitoneally at various doses twice weekly for 4 weeks. Syngeneic T-cell-deficient mice, B-cell-deficient mice, recombination activating gene 2-deficient (RAG2-KO) mice and RAG2-KO mice that had been reconstituted with CD4+ or CD8+ T cells isolated from WT mice were treated with zymosan similarly. Mice were killed, the severity of pancreatitis was graded histologically, and serum cytokine levels were measured. RESULTS: Repeated administration of zymosan induced pancreatitis dose dependently in both WT and IL-10-KO mice. Administration of LTA induced pancreatitis only in IL-10-KO mice. Adoptive transfer of splenocytes obtained from IL-10-KO mice with pancreatitis did not cause pancreatitis in recipient RAG2-KO mice. Pancreatitis was scarcely observed in RAG2-KO mice and was attenuated in T-cell-deficient and B-cell-deficient mice compared with WT mice. A single administration of zymosan significantly increased the serum level of monocyte chemoattractant protein 1 (MCP-1) in WT mice. CONCLUSIONS: Repeated stimulation of TLR2 and dectin-1 induced nonautoimmune-mediated pancreatitis in mice. Participation of acquired immunity seems to play an important role in the pathogenesis of pancreatitis in association with the increase in serum MCP-1 level.
BACKGROUND: Stimulation of Toll-like receptor 3 (TLR3) induces autoimmune-mediated pancreatitis in susceptible mice, whereas stimulation of TLR4 causes nonautoimmune-mediated pancreatitis. However, the effects of TLR2 stimulation on the pancreas are unknown. AIMS: We investigated the role of TLR2 stimulation on pancreatic damage by repeatedly stimulating mice with TLR2 ligands. METHODS: Wild-type (WT) and interleukin 10-deficient (IL-10-knockout (KO)) mice were administered zymosan and lipoteichoic acid (LTA) intraperitoneally at various doses twice weekly for 4 weeks. Syngeneic T-cell-deficient mice, B-cell-deficient mice, recombination activating gene 2-deficient (RAG2-KO) mice and RAG2-KO mice that had been reconstituted with CD4+ or CD8+ T cells isolated from WT mice were treated with zymosan similarly. Mice were killed, the severity of pancreatitis was graded histologically, and serum cytokine levels were measured. RESULTS: Repeated administration of zymosan induced pancreatitis dose dependently in both WT and IL-10-KO mice. Administration of LTA induced pancreatitis only in IL-10-KO mice. Adoptive transfer of splenocytes obtained from IL-10-KO mice with pancreatitis did not cause pancreatitis in recipient RAG2-KO mice. Pancreatitis was scarcely observed in RAG2-KO mice and was attenuated in T-cell-deficient and B-cell-deficient mice compared with WT mice. A single administration of zymosan significantly increased the serum level of monocyte chemoattractant protein 1 (MCP-1) in WT mice. CONCLUSIONS: Repeated stimulation of TLR2 and dectin-1 induced nonautoimmune-mediated pancreatitis in mice. Participation of acquired immunity seems to play an important role in the pathogenesis of pancreatitis in association with the increase in serum MCP-1 level.
Authors: Dhiraj Yadav; Lawrence Timmons; Joanne T Benson; Ross A Dierkhising; Suresh T Chari Journal: Am J Gastroenterol Date: 2011-09-27 Impact factor: 10.864
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