A NONGENOMIC MECHANISM FOR PROGESTERONE-MEDIATED IMMUNOSUPPRESSION - INHIBITION OF K-EXPRESSION IN T-LYMPHOCYTES( CHANNELS, CA2+ SIGNALING,AND GENE)

The mechanism by which progesterone causes localized suppression of th e immune response during pregnancy has remained elusive. Using human T lymphocytes and T cell lines, we show that progesterone, at concentra tions found in the placenta, rapidly and reversibly blocks voltage-gat ed and calcium-activated K+ channels (K-v and K-Ca, respectively), res ulting in depolarization of the membrane potential. As a result, Ca2signaling and nuclear factor of activated T cells (NF-AT)-driven gene expression are inhibited. Progesterone acts distally to the initial st eps of T cell receptor (TCR)-mediated signal transduction, since it bl ocks sustained Ca2+ signals after thapsigargin stimulation, as well as oscillatory Ca2+ signals, but not the Ca2+ transient after TCR stimul ation. K+ channel blockade by progesterone is specific; other steroid hormones had little or no effect, although the progesterone antagonist RU 486 also blocked K-v and K-Ca channels. Progesterone effectively b locked a broad spectrum of K+ channels, reducing both Kv1.3 and charyb dotoxin-resistant components of K-v current and K-Ca current in T cell s, as well as blocking several cloned K-v channels expressed in cell l ines. Progesterone had little or no effect on a cloned voltage-gated N a+ channel, an inward rectifier K+ channel, or on lymphocyte Ca2+ and Cl- channels. We propose that direct inhibition of K+ channels in T ce lls by progesterone contributes to progesterone-induced immunosuppress ion.