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 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.
Samy
Eileen T
ET
Inflammation, Autoimmunity, and Transplantation Research, Roche Palo Alto, Palo Alto, CA 94304, USA.
Meyer
Claas A
CA
Caplazi
Patrick
P
Langrish
Claire L
CL
Lora
Jose M
JM
Bluethmann
Horst
H
Peng
Stanford L
SL
D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D015212:Inflammatory Bowel Diseases / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D007376:Interleukin-2 / Q000276:immunology* / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000276:immunology*; D008246:Lysophospholipids / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology; D000099157:Sphingosine Kinase
D007376:Interleukin-2; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D013110:Sphingosine; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate