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©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
Kynurenine plays an immunosuppressive role in 2,4,6-trinitrobenzene sulfate-induced colitis in mice
Chieko Tashita, Masato Hoshi, Akihiro Hirata, Kentaro Nakamoto, Tatsuya Ando, Takayuki Hattori, Yasuko Yamamoto, Hiroyuki Tezuka, Hiroyuki Tomita, Akira Hara, Kuniaki Saito
Chieko Tashita, Kentaro Nakamoto, Tatsuya Ando, Yasuko Yamamoto, Kuniaki Saito, Department of Disease Control and Prevention, Fujita Health University Graduate School of Health Sciences, Toyoake 470-1192, Japan
Masato Hoshi, Department of Biochemical and Analytical Science, Fujita Health University Graduate School of Health Sciences, Toyoake 470-1192, Japan
Akihiro Hirata, Division of Animal Experiment, Life Science Research Center, Gifu University, Gifu 501-1193, Japan
Tatsuya Ando, Hiroyuki Tezuka, Department of Cellular Function Analysis, Research Promotion and Support Headquarters, Fujita Health University Graduate School of Health Sciences, Toyoake 470-1192, Japan
Takayuki Hattori, Faculty of Medical Technology, Gifu University of Medical Science, Gifu 501-3892, Japan
Hiroyuki Tomita, Akira Hara, Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu 501-1193, Japan
Author contributions: Hoshi M, Hara A, and Saito K planned the studies; Tashita C, Hoshi M, Hirata A, Tezuka H, Hattori T, Yamamoto Y, and Tomita H performed the experiments; Tashita C and Hoshi M had responsibility for all data integrity and data analysis; Tashita C, Hoshi M, Hirata A, Tezuka H, Nakamoto K, Ando T, Hattori T, Yamamoto Y, Tomita H, Hara A, and Saito K discussed the results; Tashita C, Hoshi M, and Tezuka H wrote the manuscript; Hara A and Saito K conducted the research; Saito K had primary responsibility for the final content; all authors reviewed and approved the manuscript.
Supported by Grants-in-Aids for Young Scientists (B) from the Japan Society for the Promotion of Science, No. 17K15785; and Fujita Health University Grant (2018).
Institutional review board statement: This research was approved by the Ethics Committee of Fujita Health University.
Institutional animal care and use committee statement: This research was approved by Animal Experimental Ethical Inspection of Fujita Health University, NO. APU19040.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Masato Hoshi, PhD, Assistant Professor, Department of Biochemical and Analytical Science, Fujita Health University Graduate School of Health Sciences, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake 470-1192, Japan.
mhoshi@fujita-hu.ac.jp
Received: November 5, 2019
Peer-review started: November 5, 2019
First decision: December 23, 2019
Revised: January 6, 2020
Accepted: February 21, 2020
Article in press: February 21, 2020
Published online: March 7, 2020
Processing time: 122 Days and 6.6 Hours
BACKGROUND
Inflammatory bowel disease, such as Crohn’s disease and ulcerative colitis, is characterized by chronic intestinal inflammation leading to intestinal mucosal damage. Inflammatory bowel disease causes dysregulation of mucosal T cell responses, especially the responses of CD4+ T cells. Previously, we demonstrated that indoleamine-2,3-dioxygenase plays an immunosuppressive role in 2,4,6-trinitrobenzene sulfate (TNBS)-induced colitis. Although indoleamine-2,3-dioxygenase exerts immunosuppressive effects by altering the local concentration of tryptophan (Trp) and immunomodulatory Trp metabolites, the specific changes in immune regulation during colitis caused by Trp metabolites and its related enzymes remain unclear.
AIM
To investigate role of kynurenine 3-monooxygenase (KMO) in TNBS-induced colitis and involvement of Trp metabolites in maintenance of intestinal homeostasis.
METHODS
Colitis was induced in eight-week-old male KMO+/+ or KMO−/− mice of C57BL/6N background using TNBS. Three days later, the colon was used for hematoxylin-eosin staining for histological grading, immunohistochemical or immunofluorescence staining for KMO, cytokines, and immune cells. Inflammatory and anti-inflammatory cytokines were measured using quantitative RT-PCR, and kynurenine (Kyn) pathway metabolites were measured by high-performance liquid chromatography. The cell proportions of colonic lamina propria and mesenteric lymph nodes were analyzed by flow cytometry.
RESULTS
KMO expression levels in the colonic mononuclear phagocytes, including dendritic cells and macrophages increased upon TNBS induction. Notably, KMO deficiency reduced TNBS-induced colitis, resulting in an increased frequency of Foxp3+ regulatory T cells and increased mRNA and protein levels of anti-inflammatory cytokines, including transforming growth factor-β and interleukin-10.
CONCLUSION
Absence of KMO reduced TNBS-induced colitis via generation of Foxp3+ regulatory T cells by producing Kyn. Thus, Kyn may play a therapeutic role in colon protection during colitis.
Core tip: The role of kynurenine 3-monooxygenase (KMO) in immune regulation was examined in KMO gene deficient mice suffering from 2,4,6-trinitrobenzene sulfate-induced colitis. We demonstrated that the expression of transforming growth factor-β and interleukin-10 in the colon of these mice was upregulated by KMO inhibition and kynurenine administration, resulting in increased incidence of regulatory T cells in the inflammatory site, where they suppress progression to colitis. Thus, administration of kynurenine plays a critical role in host protection during 2,4,6-trinitrobenzene sulfate-induced colitis.
