TY - JOUR
T1 - Sphingosine kinase 2 is required for modulation of lymphocyte traffic by FTY720
AU - Kharel, Yugesh
AU - Lee, Sangderk
AU - Snyder, Ashley H.
AU - Sheasley-O'Neill, Stacey L.
AU - Morris, Margaret A.
AU - Setiady, Yulius
AU - Zhu, Ran
AU - Zigler, Molly A.
AU - Burcin, Tracy L.
AU - Ley, Klaus
AU - Tung, Kenneth S.K.
AU - Engelhard, Victor H.
AU - Macdonald, Timothy L.
AU - Pearson-White, Sonia
AU - Lynch, Kevin R.
PY - 2005/11/4
Y1 - 2005/11/4
N2 - Immunotherapeutic drugs that mimic sphingosine 1-phosphate (S1P) disrupt lymphocyte trafficking and cause T helper and T effector cells to be retained in secondary lymphoid tissue and away from sites of inflammation. The prototypical therapeutic agent, 2-alkyl-2-amino-1,3-propanediol (FTY720), stimulates S1P signaling pathways only after it is phosphorylated by one or more unknown kinases. We generated sphingosine kinase 2 (SPHK2) null mice to demonstrate that this kinase is responsible for FTY720 phosphorylation and thereby its subsequent actions on the immune system. Both systemic and lymphocyte-localized sources of SPHK2 contributed to FTY720 induced lymphopenia. Although FTY720 was selectively activated in vivo by SPHK2, other S1P pro-drugs can be phosphorylated to cause lymphopenia through the action of additional sphingosine kinases. Our results emphasize the importance of SPHK2 expression in both lymphocytes and other tissues for immune modulation and drug metabolism.
AB - Immunotherapeutic drugs that mimic sphingosine 1-phosphate (S1P) disrupt lymphocyte trafficking and cause T helper and T effector cells to be retained in secondary lymphoid tissue and away from sites of inflammation. The prototypical therapeutic agent, 2-alkyl-2-amino-1,3-propanediol (FTY720), stimulates S1P signaling pathways only after it is phosphorylated by one or more unknown kinases. We generated sphingosine kinase 2 (SPHK2) null mice to demonstrate that this kinase is responsible for FTY720 phosphorylation and thereby its subsequent actions on the immune system. Both systemic and lymphocyte-localized sources of SPHK2 contributed to FTY720 induced lymphopenia. Although FTY720 was selectively activated in vivo by SPHK2, other S1P pro-drugs can be phosphorylated to cause lymphopenia through the action of additional sphingosine kinases. Our results emphasize the importance of SPHK2 expression in both lymphocytes and other tissues for immune modulation and drug metabolism.
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U2 - 10.1074/jbc.M506293200
DO - 10.1074/jbc.M506293200
M3 - Article
C2 - 16093248
AN - SCOPUS:27744552046
SN - 0021-9258
VL - 280
SP - 36865
EP - 36872
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 44
ER -