Journal
BIOLOGICAL & PHARMACEUTICAL BULLETIN
Volume 41, Issue 5, Pages 797-805Publisher
PHARMACEUTICAL SOC JAPAN
DOI: 10.1248/bpb.b18-00051
Keywords
ceramide kinase; ulcerative colitis; mortality
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Funding
- Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan [26460060, 26460093]
- Grants-in-Aid for Scientific Research [26460060, 26460093, 17K08303] Funding Source: KAKEN
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Sphingolipids and their metabolic enzymes are implicated in ulcerative colitis. Ceramide kinase (CerK) catalyzes the phosphorylation of ceramide to ceramide-1-phosphate (C1P). Previous studies showed the activation of CerK by the pro-inflammatory cytokine interleukin-1 beta, the C1P-induced up-regulation of prostanoids exerting protective effects against colitis, and the C1P-induced down-regulation of the pro-inflammatory cytokine tumor necrosis factor-alpha. In order to elucidate CerK/C1P functions in colitis, we examined the severity of dextran sodium sulfate (DSS)-induced colitis in wild-type (WT) and CerK deletion (CerK((-/-))) mice. Lethal responses were observed in C57BL/6 mice treated with DSS in dose- and time-dependent manners. The depletion of CerK enhanced DSS-induced lethal responses without affecting the onset of these responses. In colons from mice treated with 2.5% DSS for 10d, epithelial damage was significantly enhanced by the depletion of CerK by day 5, whereas decreases in occluding and E-cadherin levels were similar in both mice. On day 5, the DSS treatment increased spleen weights and colonic levels of cyclooxygenase-2, but not cytosolic phospholipase Ala, and induced a contractile dysfunction in the colons of both mice. The DSS-induced increase in the damage activity index score between days 5 and 10 was slightly enhanced and the decrease in this score from day 10 was slower in CerK((-/-)) mice than in WT mice. On day 7 after the DSS treatment, spleen weights slightly decreased and increased in WT and CerK((-/-)) mice, respectively. These results indicate that the depletion of CerK enhances the pathology of colitis and lethal responses in DSS-treated mice.
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