Expression of sphingosine kinase 2 in synovial fibroblasts of rheumatoid arthritis contributing to apoptosis by a sphingosine analogue, FTY720.
Gene expression profiles in synovial tissues from rheumatoid arthritis (RA) patients have yielded useful information on the pathogenetic process of the synovitis. In one group of them, sphingosine kinase 2 (SPHK2), a nuclear protein regulating cell proliferation, seemed to be highly expressed, undergoing a different pathogenetic process of synovitis. In the present study it was clarified that SPHK2 was expressed in the synovial fibroblasts of the synovial tissues obtained from the knee joints of the RA patients. In the cultured synovial fibroblasts from these patients, SPHK2 was more highly expressed than that in the human macrophage cell line, THP-1 and human dermal fibroblasts. SPHK2 was expressed in and around the nucleus and transferred to the cytoplasm and cell surface by the administration of epidermal growth factor, associated with the increased expression of sphingosine-1-phosphate. A sphingosine analogue, FTY720, which is activated by phosphorylation specifically by SPHK2, mediated apoptotic signaling of the cultured synovial fibroblasts. These findings suggest that SPHK2 may regulate the autonomous proliferation of synovial fibroblasts as one of the predisposing genes to RA and could be a target for a novel therapeutic strategy for RA.
Kamada
Kazuo
K
Department of Pathogenomics, Ehime University Graduate School of Medicine, Ehime, Japan.
Arita
Norimasa
N
Tsubaki
Takahito
T
Takubo
Nobuo
N
Fujino
Takahiro
T
Soga
Yoshiko
Y
Miyazaki
Tatsuhiko
T
Yamamoto
Haruyasu
H
Nose
Masato
M
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D000068876:Fingolimod Hydrochloride; D005455:Fluorescent Antibody Technique; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D020287:In Situ Nick-End Labeling; D018613:Microscopy, Confocal; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism*; D011409:Propylene Glycols / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013583:Synovial Membrane / Q000378:metabolism; D000099157:Sphingosine Kinase
D000068876:Fingolimod Hydrochloride; D007166:Immunosuppressive Agents; D017853:Phosphotransferases (Alcohol Group Acceptor); D011409:Propylene Glycols; D013110:Sphingosine; D000099157:Sphingosine Kinase