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 (R(2)=0.61) and IL-17A (R(2)=0.51), the mayo endoscopic subscore (R(2)=0.13), and histological inflammation (R(2)=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.

• Authors: Lars Koch Hansen, Linda Sevelsted-Møller, Maj Rabjerg, Dorte Larsen, Tine Plato Hansen, Lone Klinge, Heike Wulff, Torben Knudsen, Jens Kjeldsen, Ralf Köhler
• Journal: Journal of Crohn's & colitis (J Crohns Colitis) Vol. 8 Issue 11 Pg. 1378-91 (Nov 2014) ISSN: 1876-4479 [Electronic] England
• PMID: 24793818 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 European Crohn's and Colitis Organisation. All rights reserved.

Chemical References

• Acetamides
• Biomarkers
• CD3 Complex
• CD4 Antigens
• CD8 Antigens
• Interleukin-17
• Intermediate-Conductance Calcium-Activated Potassium Channels
• KCNN4 protein, human
• Kv1.3 Potassium Channel
• RNA, Messenger
• Receptors, IgG
• Trityl Compounds
• Tumor Necrosis Factor-alpha
• Interferon-gamma
• senicapoc

Topics

• Acetamides (pharmacology)
• Adult
• Biomarkers (metabolism)
• CD3 Complex (analysis)
• CD4 Antigens (genetics, metabolism)
• CD4-Positive T-Lymphocytes (metabolism)
• CD8 Antigens (genetics, metabolism)
• CD8-Positive T-Lymphocytes (metabolism)
• Case-Control Studies
• Cell Proliferation (drug effects)
• Cells, Cultured
• Colitis, Ulcerative (genetics, immunology, pathology)
• Cross-Sectional Studies
• Female
• Gene Expression
• Humans
• Interferon-gamma (genetics, metabolism)
• Interleukin-17 (genetics, metabolism)
• Intermediate-Conductance Calcium-Activated Potassium Channels (antagonists & inhibitors, genetics, metabolism)
• Intestinal Mucosa (immunology, pathology)
• Kv1.3 Potassium Channel (antagonists & inhibitors, genetics, metabolism)
• Lymphocytes (chemistry, drug effects, metabolism)
• Male
• Middle Aged
• RNA, Messenger (metabolism)
• Receptors, IgG (genetics, metabolism)
• Severity of Illness Index
• Trityl Compounds (pharmacology)
• Tumor Necrosis Factor-alpha (genetics, metabolism)