Abstract
Evaluation of: Oo ML, Chang SH, Thangada S et al. Engagement of S1P1-degradative mechanisms leads to vascular leak in mice. J. Clin. Invest. 121(6), 2290–2300 (2011).
The interactions between sphingosine 1-phosphate (S1P) and S1P receptors (S1PRs) mediate a wide range of biological functions in the CNS and immune and cardiovascular systems. Fingolimod (FTY720), an S1PR modulator with potent immunomodulatory effects, was recently approved to treat multiple sclerosis. Some adverse effects of fingolimod reflecting vascular leak phenomena may be mediated through endothelial S1PRs, particularly macular edema. Oo et al. characterized the molecular interactions of fingolimod phosphate and S1PR type 1 (S1P1) leading to functional antagonism – phosphorylation of S1P1 with subsequent receptor complex internalization, polyubiquitinylation and degradation. Differences along the pharmacological pathways that mediate vascular leak and lymphopenia were demonstrated, suggesting that distinct S1P1 mechanisms mediate the adverse effects and efficacy of fingolimod.
Financial & competing interests disclosure
Daniel Ontaneda is supported by National Multiple Sclerosis Clinical Fellowship Award FP 1769-A-1. Jeffrey A Cohen reports having received personal compensation for consulting or speaking from Biogen Idec, Elan, Lilly, Novartis, Teva and Vaccinex. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Notes
†Possibly related to vascular leak phenomena.
‡Probably related to vascular leak phenomena.
§Possibly related to nitric oxide endothelial-associated smooth muscle effects.
¶Possible endothelial prothrombotic effects.