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Repeated Stimulation of Toll-Like Receptor 2 and Dectin-1 Induces Chronic Pancreatitis in Mice Through the Participation of Acquired Immunity

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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.

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Acknowledgments

This study was supported in part by Grants-in-Aid for Scientific Research 24591021, 26461038, 15K09053, and 17K09468 from the Japan Society for the Promotion of Science and by a Health and Labor Science Research Grant for Intractable Diseases from the Japanese Ministry of Health, Labor and Welfare.

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Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, Japan

    Masahiro Takeo, Masataka Masuda, Toshiro Fukui, Makoto Naganuma & Kazuichi Okazaki

  2. Department of Gastroenterology and Hepatology, Kansai Medical University Medical Center, 10-15 Fumizono-cho, Moriguchi, Osaka, 570-8507, Japan

    Akiyoshi Nishio, Kazunori Aoi & Takashi Okazaki

  3. Department of Gastroenterology and Hepatology, Kochi Medical School, 185-1 Kohasu Okocho, Nankoku, Kochi, Japan

    Kazushige Uchida

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  1. Masahiro Takeo
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Correspondence to Akiyoshi Nishio.

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Takeo, M., Nishio, A., Masuda, M. et al. Repeated Stimulation of Toll-Like Receptor 2 and Dectin-1 Induces Chronic Pancreatitis in Mice Through the Participation of Acquired Immunity. Dig Dis Sci 67, 3783–3796 (2022). https://doi.org/10.1007/s10620-021-07186-w

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