A role for sphingosine kinase 1 in dextran sulfate sodium-induced colitis
A role for sphingosine kinase 1 in dextran sulfate sodium-induced colitis
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DOI：
10.1096/fj.08-118109
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发表时间：
2009-01-01
期刊：
影响因子：
4.8
通讯作者：
Obeid, Lina M.
中科院分区：
文献类型：
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作者：
Snider, Ashley J.;Kawamori, Toshihiko;Obeid, Lina M.
生物活性脂鞘氨醇-1-磷酸(S1P)是一种重要的免疫和炎症反应介质。S1P的形成是由鞘氨醇激酶(SK)催化的，其中SK1同工酶由肿瘤坏死因子α(TNF-α)激活。SK1被证明是介导细胞中的肿瘤坏死因子-α炎症反应所必需的，包括诱导环氧合酶-2(COX-2)。由于炎症性肠病(IBD)患者体内的肿瘤坏死因子-α和环氧合酶-2水平升高，我们研究了SK1在小鼠结肠炎模型中的作用。与野生型(WT)小鼠相比，使用葡聚糖硫酸钠(DSS)治疗的SK1(-/-)小鼠的失血量、体重损失、结肠缩短、结肠组织学损伤和脾肿大显著减少。此外，SK1(-/-)小鼠没有全身炎症反应。此外，用葡聚糖硫酸钠治疗的WT而不是SK1(-/-)小鼠的血液S1P水平、结肠SK1消息和活性以及结肠中性粒细胞渗出显著增加。与WT小鼠不同，SK1(-/-)小鼠没有表现出结肠COX-2的诱导，尽管有被夸大的肿瘤坏死因子-α反应；因此第一次暗示SK1在体内参与了肿瘤坏死因子-α介导的COX-2诱导。抑制SK1可能通过抑制IBD的全身和局部炎症而被证明是一个有价值的治疗目标。-Snider，A.J.，Kawamori，T.，Bradshaw，S.G.，Orr，K.A.，Gilkeon，G.S.，Hannun，Y.A.，Obeid，L.M.鞘氨醇激酶1在葡聚糖硫酸钠诱导的结肠炎中的作用。FASE B J.23,143-152(2009)
The bioactive lipid sphingosine-1-phosphate (S1P) is emerging as an important mediator of immune and inflammatory responses. S1P formation is catalyzed by sphingosine kinase (SK), of which the SK1 isoenzyme is activated by tumor necrosis alpha (TNF-alpha). SK1 has been shown to be required for mediating TNF-alpha inflammatory responses in cells, including induction of cyclooxygenase 2 (COX-2). Because TNF-alpha and COX-2 are increased in patients with inflammatory bowel disease (IBD), we investigated the role of SK1 in a murine model of colitis. SK1(-/-) mice treated with dextran sulfate sodium (DSS) had significantly less blood loss, weight loss, colon shortening, colon histological damage, and splenomegaly than did wild-type (WT) mice. In addition, SK1(-/-) mice had no systemic inflammatory response. Moreover, WT but not SK1(-/-) mice treated with dextran sulfate sodium had significant increases in blood S1P levels, colon SK1 message and activity, and colon neutrophilic infiltrate. Unlike WT mice, SK1(-/-) mice failed to show colonic COX-2 induction despite an exaggerated TNF-alpha response; thus implicating for the first time SK1 in TNF-alpha-mediated COX-2 induction in vivo. Inhibition of SK1 may prove to be a valuable therapeutic target by inhibiting systemic and local inflammation in IBD.-Snider, A. J., Kawamori, T., Bradshaw, S. G., Orr, K. A., Gilkeson, G. S., Hannun, Y. A., Obeid, L. M. A role for sphingosine kinase 1 in dextran sulfate sodium-induced colitis. FASEB J. 23, 143-152 (2009)