Facilitation of colonic T cell immune responses is associated with an exacerbation of dextran sodium sulfate–induced colitis in mice lacking microsomal prostaglandin E synthase-1

Inflammation and Regeneration

Koh-ichi Yuhki¹  Fumitaka Ushikubi¹  Yoshitaka Imamichi¹  Hitoshi Kashiwagi¹  Yuka Hioki²  Fumiaki Kojima³  Hiroki Sekiya⁴  Takafumi Ichikawa⁵  Masaki Nakamura⁶  Shotaro Maehana⁶  Hidero Kitasato⁶  Makoto Kubo⁷ 

[1] Department of Pharmacology, Asahikawa Medical University, 2-1-1-1 Midorigaoka higashi, 078-8510, Asahikawa, Japan;Department of Pharmacology, Kitasato University School of Allied Health Sciences, 1-15-1 Kitasato, 252-0373, Sagamihara, Japan;Department of Pharmacology, Kitasato University School of Allied Health Sciences, 1-15-1 Kitasato, 252-0373, Sagamihara, Japan;Department of Regulation Biochemistry, Kitasato University Graduate School of Medical Sciences, 1-15-1 Kitasato, 252-0373, Sagamihara, Japan;Regenerative Medicine and Cell Design Research Facility, 1-15-1 Kitasato, 252-0373, Sagamihara, Japan;Department of Regulation Biochemistry, Kitasato University Graduate School of Medical Sciences, 1-15-1 Kitasato, 252-0373, Sagamihara, Japan;Department of Regulation Biochemistry, Kitasato University Graduate School of Medical Sciences, 1-15-1 Kitasato, 252-0373, Sagamihara, Japan;Regenerative Medicine and Cell Design Research Facility, 1-15-1 Kitasato, 252-0373, Sagamihara, Japan;Regenerative Medicine and Cell Design Research Facility, 1-15-1 Kitasato, 252-0373, Sagamihara, Japan;Department of Environmental Microbiology, Kitasato University Graduate School of Medical Sciences, 1-15-1 Kitasato, 252-0373, Sagamihara, Japan;Regenerative Medicine and Cell Design Research Facility, 1-15-1 Kitasato, 252-0373, Sagamihara, Japan;Division of Clinical Immunology, Graduate School of Medical Sciences, Kitasato University, 1-15-1 Kitasato, Minami-ku, 252-0373, Sagamihara, Japan;

关键词: Inflammatory bowel disease;    Colitis;    Immunity;    Th17 and Th1 response;    Cytokine;    Cyclooxygenase;    Prostaglandin E synthase;    Prostaglandin E;   

DOI  :  10.1186/s41232-021-00188-1

来源: Springer

【 摘 要 】

BackgroundMicrosomal prostaglandin E synthase-1 (mPGES-1) is a key enzyme that acts downstream of cyclooxygenase and plays a major role in inflammation by converting prostaglandin (PG) H2 to PGE2. The present study investigated the effect of genetic deletion of mPGES-1 on the development of immunologic responses to experimental colitis induced by dextran sodium sulfate (DSS), a well-established model of inflammatory bowel disease (IBD).MethodsColitis was induced in mice lacking mPGES-1 (mPGES-1−/− mice) and wild-type (WT) mice by administering DSS for 7 days. Colitis was assessed by body weight loss, diarrhea, fecal bleeding, and histological features. The colonic expression of mPGES-1 was determined by real-time PCR, western blotting, and immunohistochemistry. The impact of mPGES-1 deficiency on T cell immunity was determined by flow cytometry and T cell depletion in vivo.ResultsAfter administration of DSS, mPGES-1−/− mice exhibited more severe weight loss, diarrhea, and fecal bleeding than WT mice. Histological analysis further showed significant exacerbation of colonic inflammation in mPGES-1−/− mice. In WT mice, the colonic expression of mPGES-1 was highly induced on both mRNA and protein levels and colonic PGE2 increased significantly after DSS administration. Additionally, mPGES-1 protein was localized in the colonic mucosal epithelium and infiltrated inflammatory cells in underlying connective tissues and the lamina propria. The abnormalities consistent with colitis in mPGES-1−/− mice were associated with higher expression of colonic T-helper (Th)17 and Th1 cytokines, including interleukin 17A and interferon-γ. Furthermore, lack of mPGES-1 increased the numbers of Th17 and Th1 cells in the lamina propria mononuclear cells within the colon, even though the number of suppressive regulatory T cells also increased. CD4+ T cell depletion effectively reduced symptoms of colitis as well as colonic expression of Th17 and Th1 cytokines in mPGES-1−/− mice, suggesting the requirement of CD4+ T cells in the exacerbation of DSS-induced colitis under mPGES-1 deficiency.ConclusionsThese results demonstrate that mPGES-1 is the main enzyme responsible for colonic PGE2 production and deficiency of mPGES-1 facilitates the development of colitis by affecting the development of colonic T cell–mediated immunity. mPGES-1 might therefore impact both the intestinal inflammation and T cell–mediated immunity associated with IBD.

【 授权许可】

CC BY