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.

Role of epithelial ion transports in inflammatory bowel disease

“…In the human small intestine mucosa they are expressed in Paneth cells (128), probably contributing to the release of antimicrobial peptides (10), and intraepithelial leukocytes (128), where they participate in proinflammatory processes. In fact IK are, alongside K v 1.3 (73), crucial for T cell activation and proliferation: they keep an electrical gradient that allows Ca 2ϩ influx, which is a required step for the translocation of the nuclear factor of activated T cells (NFAT) to the nucleus, ultimately resulting in cytokine secretion and T cell proliferation (20,62). Given that IBD is a T cell-driven disease, it is unsurprising that inhibition of lymphocytic IK channels reduces inflammation and colitis manifestations, and therefore IK blockade has received considerable attention as a potential therapeutic target (38,53,106,132 …”

Altered calcium influx of peripheral Th2 cells in pediatric Crohn's disease: infliximab may normalize activation patterns

“…Application of selective blockers of the IKCa1 and Kv1.3 potassium channels is a possible new target for autoimmune therapy [21], and in a colitis murine model they already proved to be effective and fairly selective for the over-activated cell types [22]. In our study we could justify that both MGTX and TRAM has the potential to lower the increased calcium influx in Th2 cells nearly to the level observed in healthy individuals in case of the conventionally treated group.…”

Lymphocyte Kv1.3-channels in the pathogenesis of chronic obstructive pulmonary disease: novel therapeutic implications of targeting the channels by commonly used drugs

“…Patch-clamp studies revealed that the channels play crucial roles in facilitating the calcium influx necessary to trigger the lymphocyte activation and proliferation [11, 12]. In pathological conditions, such as in chronic kidney disease (CKD) or inflammatory bowel disease (IBD), the channels were overexpressed in proliferating lymphocytes within the inflamed kidneys or intestines, and the over-activation of the channels largely contributed to the progression of the diseases [13–15]. Previously, we demonstrated in an animal study that the overexpression of Kv1.3-channels in lymphocytes was deeply associated with their in situ proliferation in kidneys and the progression of chronic renal failure (CRF) [13].…”