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<sup>+</sup> 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<sup>+</sup> and 23% of CD8<sup>+</sup> 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 (R<sup>2</sup>=0.61) and IL-17A (R<sup>2</sup>=0.51), the mayo endoscopic subscore (R<sup>2</sup>=0.13), and histological inflammation (R<sup>2</sup>=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 | |
| State | Published - 2014 |
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Keywords
- Colitis ulcerosa;
- Interleukins;
- K<inf>Ca</inf>3.1
- KCNA3;
- KCNN4;
- Novel treatment strategy;
ASJC Scopus subject areas
- Gastroenterology
Cite this
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
}
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;
UR - http://www.scopus.com/inward/record.url?scp=84927786835&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84927786835&partnerID=8YFLogxK
U2 - 10.1016/j.crohns.2014.04.003
DO - 10.1016/j.crohns.2014.04.003
M3 - Article
C2 - 24793818
AN - SCOPUS:84927786835
VL - 8
SP - 1378
EP - 1391
JO - Journal of Crohn's and Colitis
JF - Journal of Crohn's and Colitis
SN - 1873-9946
IS - 11
ER -