Sphingosine kinase 2 is required for modulation of lymphocyte traffic by FTY720.
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.
Kharel
Yugesh
Y
Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, USA.
Lee
Sangderk
S
Snyder
Ashley H
AH
Sheasley-O'neill
Stacey L
SL
Morris
Margaret A
MA
Setiady
Yulius
Y
Zhu
Ran
R
Zigler
Molly A
MA
Burcin
Tracy L
TL
Ley
Klaus
K
Tung
Kenneth S K
KS
Engelhard
Victor H
VH
Macdonald
Timothy L
TL
Pearson-White
Sonia
S
Lynch
Kevin R
KR
D000818:Animals; D000068876:Fingolimod Hydrochloride; D005434:Flow Cytometry; D006720:Homozygote; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000633:toxicity*; D008214:Lymphocytes / Q000187:drug effects* / Q000201:enzymology*; D008231:Lymphopenia / Q000139:chemically induced / Q000201:enzymology; D008246:Lysophospholipids / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation / Q000187:drug effects; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000502:physiology*; D011355:Prodrugs / Q000378:metabolism / Q000633:toxicity; D011409:Propylene Glycols / Q000378:metabolism / Q000633:toxicity*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D000099157:Sphingosine Kinase
D000068876:Fingolimod Hydrochloride; D007166:Immunosuppressive Agents; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D011355:Prodrugs; D011409:Propylene Glycols; D013110:Sphingosine; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate