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Cited by 163Ion channel regulation and functionReproductive System and PregnancyEstrogen and related hormone effects

A nongenomic mechanism for progesterone-mediated immunosuppression: inhibition of K+ channels, Ca2+ signaling, and gene expression in T lymphocytes

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Ehring, George R., Kerschbaum, Hubert H., Eder, Claudia, Neben, Amber L., Fanger, Christopher M., Khoury, Rosana M., Negulescu, Paul A., Cahalan, Michael D.·1998·The Journal of Experimental Medicine
DOI 10.1084/jem.188.9.1593PMC PMC2212508
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Abstract

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.

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  • The Hill function fits stimulus-response data in a wide set of biological systems.

    “This agrees with general evidence that the Hill function fits stimulus-response data in a wide set of biological systems [123–128].”

    From Fibromyalgia pathogenesis explained by a neuroendocrine multistable model (2024) · cites this paper as [127]

    The Results section reports a concentration-dependent effect of progesterone on T-cell potassium currents, but does not say the data were fitted with a Hill function. Searches for “Hill” and dose–response fitting found no passage supporting the broader claim about fits across biological systems. Page numbers were not available in our copy. (LLM, conf=0.74)

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References 62 · Cited by 163

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Authors
Ehring, G. R., Kerschbaum, H. H., Eder, C., Neben, A. L., Fanger, C. M., Khoury, R. M., Negulescu, P. A., & Cahalan, M. D.
Affiliations
University of California, Irvine (US)
Corresponding author
Eder, Claudia
ORCID
Venue
The Journal of Experimental Medicine
Publisher
Rockefeller University Press
Published
1998-11-02
Volume
188
Issue
9
Pages
1593-1602
ISSN
  • 0022-1007 (ISSN-L)
  • 1540-9538
DOI
10.1084/jem.188.9.1593
PMC
PMC2212508
OpenAlex
W2117176042
Cited by
163
References
62
Citations by year
2025: 5 · 2024: 3 · 2023: 1 · 2022: 6 · 2021: 3 · 2020: 1 · 2019: 7 · 2018: 3 · 2017: 1 · 2016: 6 · 2015: 8 · 2014: 4 · 2013: 6 · 2012: 5
FWCI
3.50
Type
journal article
Language
en
Open access
Licence
cc-by-nc-sa
Locations
  • The Journal of Experimental Medicine (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • St George's Online Research Archive (St George's University of London) (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
Funders
  • National Institute of General Medical Sciences (GM-41514, R01GM041514)
  • National Institute of Neurological Disorders and Stroke (R37NS014609, R01NS014609, NS-14609, R56NS014609)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
  • Life Sciences › Immunology and Microbiology › Immunology › Reproductive System and Pregnancy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
Keywords
progesterone, immunosuppression, pregnancy, T cells, voltage-gated potassium channels, calcium-activated potassium channels, membrane depolarization, calcium signaling, NFAT, gene expression, T cell receptor signaling, Kv1.3 potassium channel, RU486, placenta
MeSH terms
Amino Acid Sequence, Cell Line, DNA-Binding Proteins, Female, Humans, Immune Tolerance, Male, Maternal-Fetal Exchange, Nuclear Proteins, Ovalbumin, Peptide Fragments, Placenta, Pregnancy, Progesterone, Receptors, Antigen, T-Cell, T-Lymphocytes, Transcription Factors, Gene Expression, Chloride Channels, Calcium Signaling, Potassium Channel Blockers, NFATC Transcription Factors

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