title: The rapid immunosuppression in phytohemagglutinin-activated human T cells is inhibited by the proliferative Ca(2+) influx induced by progesterone and analogs.
abstract: Progesterone, an endogenous immunomodulator, suppresses human T-cell activation during pregnancy. A sustained Ca(2 +) influx is an important signal for T-cell proliferation after crosslinking of T-cell receptor/CD3 complexes by anti-CD3 antibodies or phytohemagglutinin (PHA). Progesterone targets cell membrane sites inducing rapid responses including elevated intracellular free calcium concentration ([Ca(2+)]i) and suppressed T-cell PHA-activated proliferation. Interestingly, both PHA and progesterone induce [Ca(2+)]i elevation, but it remains unclear whether the PHA-induced Ca(2+) influx is affected by progesterone leading to T-cell immunosuppression. Primary T-cells were isolated from human peripheral blood and the quench effect on intracellular fura-2 fluorescence of Mn(2+) was used to explore the responses to Ca(2+) influx with cell proliferation being determined by MTT assay. PHA-stimulated Ca(2+) influx was dose-dependently suppressed by progesterone and its agonist R5020, which correlated with PHA-activated T-cell proliferation inhibition. A similar dose-dependent suppression effect on cellular Ca(2+) influx and proliferation occurred with the TRPC channel inhibitor BTP2 and selective TRPC3 channel inhibitor Pyr3. In addition, two progesterone analogs, Org OD 02-0 and 20α-hydroxyprogesterone (20α-OHP), also produced dose-dependent suppression of Ca(2+) influx, but had no effect on proliferation. Finally, inhibition of PHA-activated T-cell proliferation by progesterone is further suppressed by 20α-OHP, but not by Org OD 02-0. Overall, progesterone and R5020 are able to rapidly decrease PHA-stimulated sustained Ca(2+) influx, probably via blockade of TRPC3 channels, which suppresses T-cell proliferation. Taken together, the roles of progesterone and its analogs regarding the rapid response Ca(2+) influx need to be further explored in relation to cytokine secretion and proliferation in activated T-cells.
authors.affiliation: Institute and Department of Physiology, School of Medicine, National Yang-Ming University, Taipei 11221, Taiwan, ROC.
authors.forename: Veronica Hui-Chen
authors.initials: VH
authors.lastname: Lin
authors.affiliation: Department of Nursing, Cardinal Tien Junior College of Healthcare and Management, New Taipei City 23143, Taiwan, ROC.
authors.forename: Jiann-Jong
authors.initials: JJ
authors.lastname: Chen
authors.affiliation: Proteomics Research Center, National Yang-Ming University, Taipei 11221, Taiwan, ROC.
authors.forename: Chen-Chung
authors.initials: CC
authors.lastname: Liao
authors.affiliation: Department of Medicine, Cheng Hsin General Hospital, Taipei 11220, Taiwan, ROC. Electronic address: ch6580@chgh.org.tw.
authors.forename: Shinn-Shing
authors.initials: SS
authors.lastname: Lee
authors.affiliation: Institute and Department of Physiology, School of Medicine, National Yang-Ming University, Taipei 11221, Taiwan, ROC; Graduate Institute of Basic Medical Science, College of Medicine, China Medical University, Taichung 40402, Taiwan, ROC; Department of Healthcare Administration, Asia University, Taichung 41354, Taiwan, ROC. Electronic address: eileen@ym.edu.tw.
authors.forename: Eileen Jea
authors.initials: EJ
authors.lastname: Chien
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects*; D006801:Humans; D008345:Manganese / Q000378:metabolism; D051379:Mice; D010835:Phytohemagglutinins / Q000494:pharmacology*; D011374:Progesterone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism*
chemical_list: D010835:Phytohemagglutinins; D008345:Manganese; D011374:Progesterone; D002118:Calcium
keywords: Ca(2+) influx; Progesterone; Proliferation; Rapid responses; T cells; TRPC3 channels