Loss of neutral ceramidase increases inflammation in a mouse model of inflammatory bowel disease

Ashley J. Snider, Bill X. Wu, Russell W. Jenkins, Jonathan A. Sticca, Toshihiko Kawamori, Yusuf A. Hannun, Lina M. Obeid

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

Sphingolipids are emerging as important mediators of immune and inflammatory responses. We have previously demonstrated that sphingosine-1-phosphate (S1P) and its synthetic enzyme sphingosine kinase-1 (SK1) play an important role in inflammatory bowel disease. S1P generation is dependent on SK phosphorylation of sphingosine. Generation of sphingosine results only from the breakdown of ceramide by ceramidases (CDase). In this study, we set out to determine the role of neutral CDase (nCDase) in S1P generation and inflammatory bowel disease. To this end, we established nCDase expression is increased in patients with ulcerative colitis. Using the dextran sulfate sodium (DSS)-induced colitis model, we determined nCDase activity increased in colon epithelium, but not submucosa, in wild-type (WT) mice. Following DSS, ceramide levels were elevated in colon epithelium from WT and nCDase-/- mice, while S1P levels were significantly elevated only in the epithelium of nCDase-/- mice. Similarly, cyclooxygenase-2 (Cox-2) levels were significantly elevated only in the epithelium of nCDase -/- mice. Neutral CDase-/- mice also exhibited higher endotoxin levels in circulation, as well as higher circulating levels of S1P. This increase in S1P in nCDase-/- mice was accompanied by a marked leukocytosis, most notably circulating neutrophils and lymphocytes. Taken together these data demonstrate that loss of nCDase results in an unexpected increase in S1P generation in inflammation, and suggests that nCDase may actually protect against inflammation.

Original languageEnglish (US)
Pages (from-to)124-130
Number of pages7
JournalProstaglandins and Other Lipid Mediators
Volume99
Issue number3-4
DOIs
StatePublished - Dec 2012
Externally publishedYes

Keywords

  • Ceramidase
  • Ceramide
  • Colitis
  • Inflammation
  • Neutrophil
  • Sphingosine-1-phosphate

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Pharmacology
  • Cell Biology

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