Expression of T-cell K<inf>V</inf>1.3 potassium channel correlates with pro-inflammatory cytokines and disease activity in ulcerative colitis

Lars Koch Hansen; Linda Sevelsted-Møller; Maj Rabjerg; Dorte Larsen; Tine Plato Hansen; Lone Klinge; Heike Wulff; Torben Knudsen; Jens Kjeldsen; Ralf Köhler

doi:10.1016/j.crohns.2014.04.003

Expression of T-cell K<inf>V</inf>1.3 potassium channel correlates with pro-inflammatory cytokines and disease activity in ulcerative colitis

Lars Koch Hansen, Linda Sevelsted-Møller, Maj Rabjerg, Dorte Larsen, Tine Plato Hansen, Lone Klinge, Heike Wulff, Torben Knudsen, Jens Kjeldsen, Ralf Köhler

Pharmacology

Research output: Contribution to journal › Article › peer-review

33 Scopus citations

Abstract

Background and aims: Potassium channels, K<inf>V</inf>1.3 and K<inf>Ca</inf>3.1, have been suggested to control T-cell activation, proliferation, and cytokine production and may thus constitute targets for anti-inflammatory therapy. Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by excessive T-cell infiltration and cytokine production. It is unknown if K<inf>V</inf>1.3 and K<inf>Ca</inf>3.1 in the inflamed mucosa are markers of active UC. We hypothesized that K<inf>V</inf>1.3 and K<inf>Ca</inf>3.1 correlate with disease activity and cytokine production in patients with UC. Methods: Mucosal biopsies were collected from patients with active UC (n=33) and controls (n=15). Protein and mRNA expression of K<inf>V</inf>1.3 and K<inf>Ca</inf>3.1, immune cell markers, and pro-inflammatory cytokines were determined by quantitative-real-time-polymerase-chain-reaction (qPCR) and immunofluorescence, and correlated with clinical parameters of inflammation. In-vitro cytokine production was measured in human CD3+ T-cells after pharmacological blockade of K<inf>V</inf>1.3 and K<inf>Ca</inf>3.1. Results: Active UC K<inf>V</inf>1.3 mRNA expression was increased 5-fold compared to controls. Immunofluorescence analyses revealed that K<inf>V</inf>1.3 protein was present in inflamed mucosa in 57% of CD4+ and 23% of CD8+ T-cells. K<inf>V</inf>1.3 was virtually absent on infiltrating macrophages. K<inf>V</inf>1.3 mRNA expression correlated significantly with mRNA expression of pro-inflammatory cytokines TNF-α (R2=0.61) and IL-17A (R2=0.51), the mayo endoscopic subscore (R2=0.13), and histological inflammation (R2=0.23). In-vitro blockade of T-cell K<inf>V</inf>1.3 and K<inf>Ca</inf>3.1 decreased production of IFN-γ, TNF-α, and IL-17A. Conclusions: High levels of K<inf>V</inf>1.3 in CD4 and CD8 positive T-cells infiltrates are associated with production of pro-inflammatory IL-17A and TNF-α in active UC. K<inf>V</inf>1.3 may serve as a marker of disease activity and pharmacological blockade might constitute a novel immunosuppressive strategy.

Original language	English (US)
Pages (from-to)	1378-1391
Number of pages	14
Journal	Journal of Crohn's and Colitis
Volume	8
Issue number	11
DOIs	https://doi.org/10.1016/j.crohns.2014.04.003
State	Published - 2014

Keywords

Colitis ulcerosa;
Interleukins;
K<inf>Ca</inf>3.1
KCNA3;
KCNN4;
Novel treatment strategy;

ASJC Scopus subject areas

Gastroenterology

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10.1016/j.crohns.2014.04.003

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Koch Hansen, L., Sevelsted-Møller, L., Rabjerg, M., Larsen, D., Hansen, T. P., Klinge, L., Wulff, H., Knudsen, T., Kjeldsen, J., & Köhler, R. (2014). Expression of T-cell K<inf>V</inf>1.3 potassium channel correlates with pro-inflammatory cytokines and disease activity in ulcerative colitis. Journal of Crohn's and Colitis, 8(11), 1378-1391. https://doi.org/10.1016/j.crohns.2014.04.003

Expression of T-cell K<inf>V</inf>1.3 potassium channel correlates with pro-inflammatory cytokines and disease activity in ulcerative colitis. / Koch Hansen, Lars; Sevelsted-Møller, Linda; Rabjerg, Maj; Larsen, Dorte; Hansen, Tine Plato; Klinge, Lone; Wulff, Heike; Knudsen, Torben; Kjeldsen, Jens; Köhler, Ralf.

In: Journal of Crohn's and Colitis, Vol. 8, No. 11, 2014, p. 1378-1391.

Research output: Contribution to journal › Article › peer-review

Koch Hansen, L, Sevelsted-Møller, L, Rabjerg, M, Larsen, D, Hansen, TP, Klinge, L, Wulff, H, Knudsen, T, Kjeldsen, J & Köhler, R 2014, 'Expression of T-cell K<inf>V</inf>1.3 potassium channel correlates with pro-inflammatory cytokines and disease activity in ulcerative colitis', Journal of Crohn's and Colitis, vol. 8, no. 11, pp. 1378-1391. https://doi.org/10.1016/j.crohns.2014.04.003

Koch Hansen, Lars ; Sevelsted-Møller, Linda ; Rabjerg, Maj ; Larsen, Dorte ; Hansen, Tine Plato ; Klinge, Lone ; Wulff, Heike ; Knudsen, Torben ; Kjeldsen, Jens ; Köhler, Ralf. / Expression of T-cell K<inf>V</inf>1.3 potassium channel correlates with pro-inflammatory cytokines and disease activity in ulcerative colitis. In: Journal of Crohn's and Colitis. 2014 ; Vol. 8, No. 11. pp. 1378-1391.

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title = "Expression of T-cell KV1.3 potassium channel correlates with pro-inflammatory cytokines and disease activity in ulcerative colitis",

abstract = "Background and aims: Potassium channels, KV1.3 and KCa3.1, have been suggested to control T-cell activation, proliferation, and cytokine production and may thus constitute targets for anti-inflammatory therapy. Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by excessive T-cell infiltration and cytokine production. It is unknown if KV1.3 and KCa3.1 in the inflamed mucosa are markers of active UC. We hypothesized that KV1.3 and KCa3.1 correlate with disease activity and cytokine production in patients with UC. Methods: Mucosal biopsies were collected from patients with active UC (n=33) and controls (n=15). Protein and mRNA expression of KV1.3 and KCa3.1, immune cell markers, and pro-inflammatory cytokines were determined by quantitative-real-time-polymerase-chain-reaction (qPCR) and immunofluorescence, and correlated with clinical parameters of inflammation. In-vitro cytokine production was measured in human CD3+ T-cells after pharmacological blockade of KV1.3 and KCa3.1. Results: Active UC KV1.3 mRNA expression was increased 5-fold compared to controls. Immunofluorescence analyses revealed that KV1.3 protein was present in inflamed mucosa in 57% of CD4+ and 23% of CD8+ T-cells. KV1.3 was virtually absent on infiltrating macrophages. KV1.3 mRNA expression correlated significantly with mRNA expression of pro-inflammatory cytokines TNF-α (R2=0.61) and IL-17A (R2=0.51), the mayo endoscopic subscore (R2=0.13), and histological inflammation (R2=0.23). In-vitro blockade of T-cell KV1.3 and KCa3.1 decreased production of IFN-γ, TNF-α, and IL-17A. Conclusions: High levels of KV1.3 in CD4 and CD8 positive T-cells infiltrates are associated with production of pro-inflammatory IL-17A and TNF-α in active UC. KV1.3 may serve as a marker of disease activity and pharmacological blockade might constitute a novel immunosuppressive strategy.",

keywords = "Colitis ulcerosa;, Interleukins;, K<inf>Ca</inf>3.1, KCNA3;, KCNN4;, Novel treatment strategy;",

author = "{Koch Hansen}, Lars and Linda Sevelsted-M{\o}ller and Maj Rabjerg and Dorte Larsen and Hansen, {Tine Plato} and Lone Klinge and Heike Wulff and Torben Knudsen and Jens Kjeldsen and Ralf K{\"o}hler",

year = "2014",

doi = "10.1016/j.crohns.2014.04.003",

language = "English (US)",

volume = "8",

pages = "1378--1391",

journal = "Journal of Crohn's and Colitis",

issn = "1873-9946",

publisher = "Elsevier",

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TY - JOUR

T1 - Expression of T-cell KV1.3 potassium channel correlates with pro-inflammatory cytokines and disease activity in ulcerative colitis

AU - Koch Hansen, Lars

AU - Sevelsted-Møller, Linda

AU - Rabjerg, Maj

AU - Larsen, Dorte

AU - Hansen, Tine Plato

AU - Klinge, Lone

AU - Wulff, Heike

AU - Knudsen, Torben

AU - Kjeldsen, Jens

AU - Köhler, Ralf

PY - 2014

Y1 - 2014

N2 - Background and aims: Potassium channels, KV1.3 and KCa3.1, have been suggested to control T-cell activation, proliferation, and cytokine production and may thus constitute targets for anti-inflammatory therapy. Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by excessive T-cell infiltration and cytokine production. It is unknown if KV1.3 and KCa3.1 in the inflamed mucosa are markers of active UC. We hypothesized that KV1.3 and KCa3.1 correlate with disease activity and cytokine production in patients with UC. Methods: Mucosal biopsies were collected from patients with active UC (n=33) and controls (n=15). Protein and mRNA expression of KV1.3 and KCa3.1, immune cell markers, and pro-inflammatory cytokines were determined by quantitative-real-time-polymerase-chain-reaction (qPCR) and immunofluorescence, and correlated with clinical parameters of inflammation. In-vitro cytokine production was measured in human CD3+ T-cells after pharmacological blockade of KV1.3 and KCa3.1. Results: Active UC KV1.3 mRNA expression was increased 5-fold compared to controls. Immunofluorescence analyses revealed that KV1.3 protein was present in inflamed mucosa in 57% of CD4+ and 23% of CD8+ T-cells. KV1.3 was virtually absent on infiltrating macrophages. KV1.3 mRNA expression correlated significantly with mRNA expression of pro-inflammatory cytokines TNF-α (R2=0.61) and IL-17A (R2=0.51), the mayo endoscopic subscore (R2=0.13), and histological inflammation (R2=0.23). In-vitro blockade of T-cell KV1.3 and KCa3.1 decreased production of IFN-γ, TNF-α, and IL-17A. Conclusions: High levels of KV1.3 in CD4 and CD8 positive T-cells infiltrates are associated with production of pro-inflammatory IL-17A and TNF-α in active UC. KV1.3 may serve as a marker of disease activity and pharmacological blockade might constitute a novel immunosuppressive strategy.

AB - Background and aims: Potassium channels, KV1.3 and KCa3.1, have been suggested to control T-cell activation, proliferation, and cytokine production and may thus constitute targets for anti-inflammatory therapy. Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by excessive T-cell infiltration and cytokine production. It is unknown if KV1.3 and KCa3.1 in the inflamed mucosa are markers of active UC. We hypothesized that KV1.3 and KCa3.1 correlate with disease activity and cytokine production in patients with UC. Methods: Mucosal biopsies were collected from patients with active UC (n=33) and controls (n=15). Protein and mRNA expression of KV1.3 and KCa3.1, immune cell markers, and pro-inflammatory cytokines were determined by quantitative-real-time-polymerase-chain-reaction (qPCR) and immunofluorescence, and correlated with clinical parameters of inflammation. In-vitro cytokine production was measured in human CD3+ T-cells after pharmacological blockade of KV1.3 and KCa3.1. Results: Active UC KV1.3 mRNA expression was increased 5-fold compared to controls. Immunofluorescence analyses revealed that KV1.3 protein was present in inflamed mucosa in 57% of CD4+ and 23% of CD8+ T-cells. KV1.3 was virtually absent on infiltrating macrophages. KV1.3 mRNA expression correlated significantly with mRNA expression of pro-inflammatory cytokines TNF-α (R2=0.61) and IL-17A (R2=0.51), the mayo endoscopic subscore (R2=0.13), and histological inflammation (R2=0.23). In-vitro blockade of T-cell KV1.3 and KCa3.1 decreased production of IFN-γ, TNF-α, and IL-17A. Conclusions: High levels of KV1.3 in CD4 and CD8 positive T-cells infiltrates are associated with production of pro-inflammatory IL-17A and TNF-α in active UC. KV1.3 may serve as a marker of disease activity and pharmacological blockade might constitute a novel immunosuppressive strategy.

KW - Colitis ulcerosa;

KW - Interleukins;

KW - K<inf>Ca</inf>3.1

KW - KCNA3;

KW - KCNN4;

KW - Novel treatment strategy;

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Expression of T-cell K<inf>V</inf>1.3 potassium channel correlates with pro-inflammatory cytokines and disease activity in ulcerative colitis

Abstract

Keywords

ASJC Scopus subject areas

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