Loss of neutral ceramidase increases inflammation in a mouse model of inflammatory bowel disease.
Prostaglandins Other Lipid Mediat
; 99(3-4): 124-30, 2012 Dec.
Article
em En
| MEDLINE
| ID: mdl-22940715
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Esfingosina
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Lisofosfolipídeos
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Colite Ulcerativa
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Colo
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Ceramidase Neutra
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Inflamação
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Mucosa Intestinal
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Leucocitose
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Prostaglandins Other Lipid Mediat
Assunto da revista:
ENDOCRINOLOGIA
Ano de publicação:
2012
Tipo de documento:
Article
País de afiliação:
Estados Unidos