Inhibition of the K+ channel KCa3.1 ameliorates T cell-mediated colitis

Lie Di, Shekhar Srivastava, Olga Zhdanova, Yi Ding, Zhai Li, Heike Wulff, Maria Lafaille, Edward Y. Skolnik

Research output: Contribution to journalArticle

87 Citations (Scopus)

Abstract

The calcium-activated K+ channel KCa3.1 plays an important role in T lymphocyte Ca2+ signaling by helping to maintain a negative membrane potential, which provides an electrochemical gradient to drive Ca 2+ influx. To assess the role of KCa3.1 channels in lymphocyte activation in vivo, we studied T cell function in KCa3.1-/- mice. CD4 T helper (i.e., Th0) cells isolated from KCa3.1-/- mice lacked KCa3.1 channel activity, which resulted in decreased T cell receptor-stimulated Ca2+ influx and IL-2 production. Although loss of KCa3.1 did not interfere with CD4 T cell differentiation, both Ca2+ influx and cytokine production were impaired in KCa3.1-/- Th1 and Th2 CD4 T cells, whereas T regulatory and Th17 function were normal. We found that inhibition of KCa3.1-/- protected mice from developing severe colitis in two mouse models of inflammatory bowel disease, which were induced by (i) the adoptive transfer of mouse naïve CD4T cells into rag2-/- recipients and (ii) trinitrobenzene sulfonic acid. Pharmacologic inhibitors of KCa3.1 have already been shown to be safe in humans. Thus, if these preclinical studies continue to show efficacy, it may be possible to rapidly test whether KCa3.1 inhibitors are efficacious in patients with inflammatory bowel diseases such as Crohn's disease and ulcerative colitis.

Original languageEnglish (US)
Pages (from-to)1541-1546
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number4
DOIs
StatePublished - Jan 26 2010

Fingerprint

Colitis
T-Lymphocytes
Inflammatory Bowel Diseases
Trinitrobenzenes
Calcium-Activated Potassium Channels
Sulfonic Acids
Adoptive Transfer
Lymphocyte Activation
T-Cell Antigen Receptor
Ulcerative Colitis
Crohn Disease
Membrane Potentials
Interleukin-2
Cell Differentiation
Cytokines

Keywords

  • Calcium signaling
  • Inflammatory bowel disease
  • Potassium channels
  • T helper cells
  • T-cell signaling

ASJC Scopus subject areas

  • General

Cite this

Inhibition of the K+ channel KCa3.1 ameliorates T cell-mediated colitis. / Di, Lie; Srivastava, Shekhar; Zhdanova, Olga; Ding, Yi; Li, Zhai; Wulff, Heike; Lafaille, Maria; Skolnik, Edward Y.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 4, 26.01.2010, p. 1541-1546.

Research output: Contribution to journalArticle

Di, Lie ; Srivastava, Shekhar ; Zhdanova, Olga ; Ding, Yi ; Li, Zhai ; Wulff, Heike ; Lafaille, Maria ; Skolnik, Edward Y. / Inhibition of the K+ channel KCa3.1 ameliorates T cell-mediated colitis. In: Proceedings of the National Academy of Sciences of the United States of America. 2010 ; Vol. 107, No. 4. pp. 1541-1546.
@article{574b3b7a6a8d4435bc29f04f581d24e7,
title = "Inhibition of the K+ channel KCa3.1 ameliorates T cell-mediated colitis",
abstract = "The calcium-activated K+ channel KCa3.1 plays an important role in T lymphocyte Ca2+ signaling by helping to maintain a negative membrane potential, which provides an electrochemical gradient to drive Ca 2+ influx. To assess the role of KCa3.1 channels in lymphocyte activation in vivo, we studied T cell function in KCa3.1-/- mice. CD4 T helper (i.e., Th0) cells isolated from KCa3.1-/- mice lacked KCa3.1 channel activity, which resulted in decreased T cell receptor-stimulated Ca2+ influx and IL-2 production. Although loss of KCa3.1 did not interfere with CD4 T cell differentiation, both Ca2+ influx and cytokine production were impaired in KCa3.1-/- Th1 and Th2 CD4 T cells, whereas T regulatory and Th17 function were normal. We found that inhibition of KCa3.1-/- protected mice from developing severe colitis in two mouse models of inflammatory bowel disease, which were induced by (i) the adoptive transfer of mouse na{\"i}ve CD4T cells into rag2-/- recipients and (ii) trinitrobenzene sulfonic acid. Pharmacologic inhibitors of KCa3.1 have already been shown to be safe in humans. Thus, if these preclinical studies continue to show efficacy, it may be possible to rapidly test whether KCa3.1 inhibitors are efficacious in patients with inflammatory bowel diseases such as Crohn's disease and ulcerative colitis.",
keywords = "Calcium signaling, Inflammatory bowel disease, Potassium channels, T helper cells, T-cell signaling",
author = "Lie Di and Shekhar Srivastava and Olga Zhdanova and Yi Ding and Zhai Li and Heike Wulff and Maria Lafaille and Skolnik, {Edward Y.}",
year = "2010",
month = "1",
day = "26",
doi = "10.1073/pnas.0910133107",
language = "English (US)",
volume = "107",
pages = "1541--1546",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "4",

}

TY - JOUR

T1 - Inhibition of the K+ channel KCa3.1 ameliorates T cell-mediated colitis

AU - Di, Lie

AU - Srivastava, Shekhar

AU - Zhdanova, Olga

AU - Ding, Yi

AU - Li, Zhai

AU - Wulff, Heike

AU - Lafaille, Maria

AU - Skolnik, Edward Y.

PY - 2010/1/26

Y1 - 2010/1/26

N2 - The calcium-activated K+ channel KCa3.1 plays an important role in T lymphocyte Ca2+ signaling by helping to maintain a negative membrane potential, which provides an electrochemical gradient to drive Ca 2+ influx. To assess the role of KCa3.1 channels in lymphocyte activation in vivo, we studied T cell function in KCa3.1-/- mice. CD4 T helper (i.e., Th0) cells isolated from KCa3.1-/- mice lacked KCa3.1 channel activity, which resulted in decreased T cell receptor-stimulated Ca2+ influx and IL-2 production. Although loss of KCa3.1 did not interfere with CD4 T cell differentiation, both Ca2+ influx and cytokine production were impaired in KCa3.1-/- Th1 and Th2 CD4 T cells, whereas T regulatory and Th17 function were normal. We found that inhibition of KCa3.1-/- protected mice from developing severe colitis in two mouse models of inflammatory bowel disease, which were induced by (i) the adoptive transfer of mouse naïve CD4T cells into rag2-/- recipients and (ii) trinitrobenzene sulfonic acid. Pharmacologic inhibitors of KCa3.1 have already been shown to be safe in humans. Thus, if these preclinical studies continue to show efficacy, it may be possible to rapidly test whether KCa3.1 inhibitors are efficacious in patients with inflammatory bowel diseases such as Crohn's disease and ulcerative colitis.

AB - The calcium-activated K+ channel KCa3.1 plays an important role in T lymphocyte Ca2+ signaling by helping to maintain a negative membrane potential, which provides an electrochemical gradient to drive Ca 2+ influx. To assess the role of KCa3.1 channels in lymphocyte activation in vivo, we studied T cell function in KCa3.1-/- mice. CD4 T helper (i.e., Th0) cells isolated from KCa3.1-/- mice lacked KCa3.1 channel activity, which resulted in decreased T cell receptor-stimulated Ca2+ influx and IL-2 production. Although loss of KCa3.1 did not interfere with CD4 T cell differentiation, both Ca2+ influx and cytokine production were impaired in KCa3.1-/- Th1 and Th2 CD4 T cells, whereas T regulatory and Th17 function were normal. We found that inhibition of KCa3.1-/- protected mice from developing severe colitis in two mouse models of inflammatory bowel disease, which were induced by (i) the adoptive transfer of mouse naïve CD4T cells into rag2-/- recipients and (ii) trinitrobenzene sulfonic acid. Pharmacologic inhibitors of KCa3.1 have already been shown to be safe in humans. Thus, if these preclinical studies continue to show efficacy, it may be possible to rapidly test whether KCa3.1 inhibitors are efficacious in patients with inflammatory bowel diseases such as Crohn's disease and ulcerative colitis.

KW - Calcium signaling

KW - Inflammatory bowel disease

KW - Potassium channels

KW - T helper cells

KW - T-cell signaling

UR - http://www.scopus.com/inward/record.url?scp=76549083562&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=76549083562&partnerID=8YFLogxK

U2 - 10.1073/pnas.0910133107

DO - 10.1073/pnas.0910133107

M3 - Article

C2 - 20080610

AN - SCOPUS:76549083562

VL - 107

SP - 1541

EP - 1546

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 4

ER -