Sphingosine Kinases promote IL-17 expression in human T lymphocytes

Abstract

Sphingosine 1-phosphate (S1P) has a role in many cellular processes. S1P is involved in cell growth and apoptosis, regulation of cell trafficking, production of cytokines and chemokines. The kinases SphK1 and SphK2 (SphKs) phosphorilate Sphingosine (Sph) to S1P and several phosphatases revert S1P to sphingosine, thus assuring a balanced pool that can be depleted by a Sphingosine lyase in hexadecenal compounds and aldehydes. There are evidences that SphK1 and 2 may per se control cellular processes. Here, we report that Sph kinases regulate IL-17 expression in human T cells. SphKs inhibition impairs the production of IL-17, while their overexpression up-regulates expression of the cytokine through acetylation of IL-17 promoter. SphKs were up-regulated also in PBMCs of patients affected by IL-17 related diseases. Thus, S1P/S1P kinases axis is a mechanism likely to promote IL-17 expression in human T cells, representing a possible therapeutic target in human inflammatory diseases.

Cytokine-Induced and Stretch-Induced Sphingosine 1-Phosphate Production by Enthesis Cells Could Favor Abnormal Ossification in Spondyloarthritis

“…Although no data are available on SpA patients, S1P concentration is elevated in the SF of osteoarthritis and rheumatoid arthritis patients (3.5μM and 17.5μM, respectively) . In addition, serum S1P concentration is higher in SpA patients than in healthy donors, as we and others have shown . The presence of EDTA in our SF samples prevented us from determining the S1P concentration with the commercially available S1P ELISA.…”

“…We can speculate that there may be positive feedback in the context of SpA, where IL-17 secreted by entheseal T cells could stimulate local S1P production, in turn amplifying inflammation. (46,47) We demonstrated that fingolimod significantly reduced the S1PR activation induced by SpA patients' SF, strongly suggesting the presence of S1P in SF (Fig. 5).…”

“…Thus, by creating a concentration gradient, the increased S1P levels may favor immune cell recruitment. In addition, it has been reported that S1P acts on Th17 mouse cells and recently, in Th17 human cells, to activate IL‐17 production. We can speculate that there may be positive feedback in the context of SpA, where IL‐17 secreted by entheseal T cells could stimulate local S1P production, in turn amplifying inflammation …”

“…S1P could be secreted (dashed arrows) and the released S1P could enhance chondrocyte hypertrophy through S1P 1 and S1P 3 . Others have shown that it can also contribute to maintaining local inflammation (light gray arrow) by stimulating Th17 enthesis resident immune cells …”

“…(32) In addition, serum S1P concentration is higher in SpA patients than in healthy donors, as we and others have shown. (19,47) The presence of EDTA in our SF samples prevented us from determining the S1P concentration with the commercially available S1P ELISA. Therefore, we are currently developing a mass spectrometry method to determine S1P in various biological fluids.…”