Non-genomic rapid responses via progesterone in human peripheral T cells are not indirectly mimicked by sphingosine 1-phosphate

Progesterone is an endogenous immunomodulator that suppresses T cell activation during pregnancy. Progesterone has been shown to induce rapid responses that cause intracellular calcium ([Ca2+],) elevation and acidification followed by inhibition of phytohemagglutinin (PHA)-stimulated proliferation. These rapid responses involve T cell plasma membrane sites, but the mechanisms remain unclear. Three new membrane progesterone receptors (mPR alpha/mPR beta/mPR gamma) have been identified as expressed in T cells. These proteins have been identified as G-protein-coupled receptors. Recently, mPRs have been classified as progestin and adipoQ receptors (PAQRs). Furthermore, they have been suggested to be alkaline ceram-idases, possibly involved in mediating sphingolipid signaling. Alkaline ceramidases are capable of converting ceramide to sphingosine, which might then be further phosphorylated sphingosine via sphingosine kinase to sphingosine 1-phosphate (SIP). This pathway could result in progesterone acting indirectly via SW on membrane sphingosine 1-phosphate receptors (S1PRs) in T cells to induce rapid responses. Therefore, our aim was to investigate whether progesterone rapid responses occur indirectly in T cells via SIP. We found that SIP induces [Ca2+] elevation however there was no change in intracellular pH. This is different from the situation with progesterone: SIP alone does not suppress PHA-stimulated cell proliferation and does not act synergistically with progesterone on the inhibition of PHA-induced cell proliferation. In contrast, S1P at 1 mu M is able to antagonize the proliferation inhibitory effect of progesterone. Thus the rapid responses that are induced by progesterone in human peripheral T cells probably do not involve indirect signaling via SIP and S1PRs. (C) 2013 Elsevier Inc. All rights reserved.