Cutting edge: Modulation of intestinal autoimmunity and IL-2 signaling by sphingosine kinase 2 independent of sphingosine 1-phosphate
Cutting edge: Modulation of intestinal autoimmunity and IL-2 signaling by sphingosine kinase 2 independent of sphingosine 1-phosphate
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DOI：
10.4049/jimmunol.179.9.5644
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发表时间：
2007-11-01
影响因子：
4.4
通讯作者：
Peng, Stanford L.
中科院分区：
文献类型：
--
作者：
Samy, Eileen T.;Meyer, Claas A.;Peng, Stanford L.
鞘氨醇激酶（Sphk）将鞘氨醇磷酸化为鞘氨醇-1磷酸（SIP），但最近发现的其亚型Sphk 2已被认为具有独特的亚细胞定位和底物特异性。我们在此证明，令人惊讶的是，Sphk 2（-/-）CD 4（+）T细胞表现出过度活化的表型，具有响应于IL-2的显著增强的增殖和细胞因子分泌，以及对调节性T细胞介导的体外抑制的敏感性降低，显然与对SIP的作用无关。这些发现似乎反映了Sphk 2抑制IL-2信号传导的需要，因为在Sphk 2（-）/（-）CD 4（+）T细胞中，IL-2诱导异常增强的STATS磷酸化，并且STATS的小干扰RNA敲低消除了它们的过度活跃表型。这一途径在生理上调节自身炎症反应，因为Sphk 2（-/-）T细胞在scid受体中诱导了更快速和更强烈的炎症性肠病。因此，Sphk 2调节T细胞中的IL-2途径，并且Sphk 2活性的调节可以在炎性和/或感染性疾病中具有治疗效用。
Sphingosine kinase (Sphk) phosphorylates sphingosine into sphingosine-1 phosphate (SIP), but its recently identified isoform Sphk2 has been suggested to have distinct subcellular localization and substrate specificity. Wee demonstrate here that, surprisingly, Sphk2(-/-) CD4(+) T cells exhibit a hyperactivated phenotype with significantly enhanced proliferation and cytokine secretion in response to IL-2 as well as reduced sensitivity to regulatory T cell-mediated suppression in vitro, apparently independent of effects upon SIP. Such findings appear to reflect a requirement for Sphk2 to suppress IL-2 signaling because, in Sphk2(-)/(-) CD4(+) T cells, IL-2 induced abnormally accentuated STATS phosphorylation and small interfering RNA knockdown of STATS abrogated their hyperactive phenotype. This pathway physiologically modulates autoinflammatory responses, because Sphk2(-/-) T cells induced more rapid and robust inflammatory bowel disease in scid recipients. Thus, Sphk2 regulates IL-2 pathways in T cells, and the modulation of Sphk2 activity may be of therapeutic utility in inflammatory and/or infectious diseases.