Immune Netw.  2020 Apr;20(2):e16. 10.4110/in.2020.20.e16.

Inhibition of RIPK3 Pathway Attenuates Intestinal Inflammation and Cell Death of Inflammatory Bowel Disease and Suppresses Necroptosis in Peripheral Mononuclear Cells of Ulcerative Colitis Patients

Affiliations
  • 1Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
  • 2Impact Biotech, Seoul 06591, Korea
  • 3College of Pharmacy, Medical Campus, Gachon University, Incheon 21936, Korea
  • 4Division of Gastroenterology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
  • 5Department of Hospital Pathology, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
  • 6Department of Medical Lifescience, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea

Abstract

Receptor-interacting serine/threonine-protein kinase (RIPK) 3 is a member of the TNF receptor-I signaling complex and mediates necroptosis, an inflammatory cell death. Ulcerative colitis (UC) is an excessive inflammatory disease caused by uncontrolled T cell activation. The current study is aimed to determine whether RIPK3 inhibitor attenuates UC development inhibiting inflammation and necroptosis using experimental colitis mice model. Dextran sulfate sodium-induced colitis mice were administered RIPK3 inhibitor (3 mg/ml) 3 times and their tissues were analyzed by immunohistochemistry. RIPK3, mixed lineage kinase domain-like (MLKL), phosphorylated MLKL, IL-17, and CD4 in colitis patient colon tissues were detected using confocal microscopy. Protein levels were measured using immunohistochemistry and ELISA. The differentiation of Th17 cells was evaluated using flow cytometry. The expression of proinflammatory cytokines and necroptosis in peripheral blood mononuclear cells from UC patients was decreased markedly by RIPK3 inhibitor treatment. We also observed that the injection of RIPK3 inhibitor improves colitis severity and protects intestinal destruction. RIPK3 inhibitor reduced necroptosis factors and proinflammatory cytokines in the colon and consequently protected colon devastation. The expression of inflammatory mediators in experimental colitis mice splenocytes was decreased significantly by RIPK3 inhibitor treatment. These results suggest that RIPK3 inhibitor ameliorates severity of experimental colitis and reduces inflammation through the inhibition of inflammatory response and necroptosis and support RIPK3-targeting substances for treatment of UC.

Keyword

RIPK3 protein; Inflammatory bowel diseases; Necroptosis; Ulcerative colitis; Inflammation
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