Chronic increases in sphingosine kinase-1 activity induce a pro-inflammatory, pro-angiogenic phenotype in endothelial cells |
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Authors: | Vidya Limaye Pu Xia Chris Hahn Malcolm Smith Mathew A Vadas Stuart M Pitson Jennifer R Gamble |
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Institution: | 1. Royal Adelaide Hospital, Department of Rheumatology, North Tce, Royal Adelaide Hospital, Adelaide, SA, 5000, Australia 2. Division of Human Immunology, Institute of Medical and Veterinary Science, Frome Road, Adelaide, SA, 5000, Australia 3. Department of Medicine, University of Adelaide, Frome Rd, Adelaide, SA, Australia 6. Centenary Institute, University of Sydney, NSW, Sydney, Australia 4. Repatriation General Hospital, Daw Park, SA, Australia 5. School of Molecular and Biomedical Science, University of Adelaide, Adelaide, Australia
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Abstract: | Sphingosine kinase-1 (SK1) promotes the formation of sphingosine-1-phosphate (S1P), which has potent pro-inflammatory and
pro-angiogenic effects. We investigated the effects of raised SK1 levels on endothelial cell function and the possibility
that this signaling pathway is activated in rheumatoid arthritis. Human umbilical vein endothelial cells with 3- to 5-fold
SK1 (ECSK) overexpression were generated by adenoviral and retroviralmediated gene delivery. The activation state of these cells and
their ability to undergo angiogenesis was determined. S1P was measured in synovial fluid from patients with RA and OA. ECSK showed an enhanced migratory capacity and a stimulated rate of capillary tube formation. The cells showed constitutive activation
as evidenced by the induction of basal VCAM-1 expression, and further showed a more augmented VCAM-1 and E selectin response
to TNF compared with empty vector control cells (ECEV). These changes had functional consequences in terms of enhanced neutrophil binding in the basal and TNFstimulated states
in ECSK. By contrast, over-expression of a dominant-negative SK inhibited the TNF-induced VCAM-1 and E selectin and inhibited PMN
adhesion, confirming that the observed effects were specifically mediated by SK. The synovial fluid levels of S1P were significantly
higher in patients with RA than in those with OA. Small chronic increases in SK1 activity in the endothelial cells enhance
the ability of the cells to support inflammation and undergo angiogenesis, and sensitize the cells to inflammatory cytokines.
The SK1 signaling pathway is activated in RA, suggesting that manipulation of SK1 activity in diseases of aberrant inflammation
and angiogenesis may be beneficial. |
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Keywords: | Inflammation Angiogenesis Endothelial cells Sphingosine kinase TNF |
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