Published online Mar 7, 2020. doi: 10.3748/wjg.v26.i9.918
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
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.
To investigate role of kynurenine 3-monooxygenase (KMO) in TNBS-induced colitis and involvement of Trp metabolites in maintenance of intestinal homeostasis.
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.
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.
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.