TY - JOUR
T1 - Kynurenine plays an immunosuppressive role in 2,4,6-trinitrobenzene sulfate-induced colitis in mice
AU - Tashita, Chieko
AU - Hoshi, Masato
AU - Hirata, Akihiro
AU - Nakamoto, Kentaro
AU - Ando, Tatsuya
AU - Hattori, Takayuki
AU - Yamamoto, Yasuko
AU - Tezuka, Hiroyuki
AU - Tomita, Hiroyuki
AU - Hara, Akira
AU - Saito, Kuniaki
N1 - Publisher Copyright:
© The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
PY - 2020/3/7
Y1 - 2020/3/7
N2 - 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-2,3dioxygenase 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.
AB - 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-2,3dioxygenase 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.
KW - Inflammatory bowie diseases
KW - Kynurenine
KW - Kynurenine 3-monooxygenase
KW - Regulatory T cell
UR - http://www.scopus.com/inward/record.url?scp=85081913848&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85081913848&partnerID=8YFLogxK
U2 - 10.3748/wjg.v26.i9.918
DO - 10.3748/wjg.v26.i9.918
M3 - Article
C2 - 32206003
AN - SCOPUS:85081913848
SN - 1007-9327
VL - 26
SP - 918
EP - 932
JO - World Journal of Gastroenterology
JF - World Journal of Gastroenterology
IS - 9
ER -