A nongenomic mechanism for progesterone-mediated immunosuppression: inhibition of K+ channels, Ca2+ signaling, and gene expression in T lymphocytes.
The mechanism by which progesterone causes localized suppression of the immune response during pregnancy has remained elusive. Using human T lymphocytes and T cell lines, we show that progesterone, at concentrations found in the placenta, rapidly and reversibly blocks voltage-gated and calcium-activated K+ channels (KV and KCa, respectively), resulting in depolarization of the membrane potential. As a result, Ca2+ signaling and nuclear factor of activated T cells (NF-AT)-driven gene expression are inhibited. Progesterone acts distally to the initial steps of T cell receptor (TCR)-mediated signal transduction, since it blocks sustained Ca2+ signals after thapsigargin stimulation, as well as oscillatory Ca2+ signals, but not the Ca2+ transient after TCR stimulation. K+ channel blockade by progesterone is specific; other steroid hormones had little or no effect, although the progesterone antagonist RU 486 also blocked KV and KCa channels. Progesterone effectively blocked a broad spectrum of K+ channels, reducing both Kv1.3 and charybdotoxin-resistant components of KV current and KCa current in T cells, as well as blocking several cloned KV channels expressed in cell lines. Progesterone had little or no effect on a cloned voltage-gated Na+ channel, an inward rectifier K+ channel, or on lymphocyte Ca2+ and Cl- channels. We propose that direct inhibition of K+ channels in T cells by progesterone contributes to progesterone-induced immunosuppression.
Ehring
G R
GR
Department of Physiology and Biophysics, University of California, Irvine, California 92697, USA.
Kerschbaum
H H
HH
Eder
C
C
Neben
A L
AL
Fanger
C M
CM
Khoury
R M
RM
Negulescu
P A
PA
Cahalan
M D
MD
D000595:Amino Acid Sequence; D020013:Calcium Signaling / Q000187:drug effects / Q000276:immunology*; D002460:Cell Line; D018118:Chloride Channels / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008431:Maternal-Fetal Exchange / Q000276:immunology; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010047:Ovalbumin / Q000235:genetics / Q000276:immunology; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology; D010920:Placenta / Q000276:immunology / Q000378:metabolism; D026902:Potassium Channel Blockers; D011247:Pregnancy; D011374:Progesterone / Q000276:immunology* / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D018118:Chloride Channels; D004268:DNA-Binding Proteins; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010446:Peptide Fragments; D026902:Potassium Channel Blockers; D011948:Receptors, Antigen, T-Cell; D014157:Transcription Factors; D011374:Progesterone; D010047:Ovalbumin