Cutting Edge: Modulation of Intestinal Autoimmunity and IL-2 Signaling by Sphingosine Kinase 2 Independent of Sphingosine 1-Phosphate

Sphingosine kinase (Sphk) phosphorylates sphingosine into sphingosine-1-phosphate (S1P), but its recently identified isoform Sphk2 has been suggested to have distinct subcellular localization and substrate specificity. We demonstrate here that, surprisingly, Sphk2(-/-) CD4(+) T cells exhibit a hyper...

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Published in:The Journal of immunology (1950) 2007-11, Vol.179 (9), p.5644-5648
Main Authors: Samy, Eileen T, Meyer, Claas A, Caplazi, Patrick, Langrish, Claire L, Lora, Jose M, Bluethmann, Horst, Peng, Stanford L
Format: Article
Language:English
Subjects:
Animals
Autoimmunity - immunology
Inflammatory Bowel Diseases - enzymology
Inflammatory Bowel Diseases - immunology
Inflammatory Bowel Diseases - pathology
Interleukin-2 - immunology
Interleukin-2 - metabolism
Intestinal Mucosa - metabolism
Intestines - immunology
Lysophospholipids - metabolism
Mice
Mice, Knockout
Phenotype
Phosphotransferases (Alcohol Group Acceptor) - deficiency
Phosphotransferases (Alcohol Group Acceptor) - genetics
Phosphotransferases (Alcohol Group Acceptor) - metabolism
Signal Transduction - immunology
Sphingosine - analogs & derivatives
Sphingosine - metabolism
T-Lymphocytes - enzymology
T-Lymphocytes - immunology
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Summary:Sphingosine kinase (Sphk) phosphorylates sphingosine into sphingosine-1-phosphate (S1P), but its recently identified isoform Sphk2 has been suggested to have distinct subcellular localization and substrate specificity. We 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 S1P. 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 STAT5 phosphorylation and small interfering RNA knockdown of STAT5 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.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.179.9.5644