Selective Inhibition of CCR7− Effector Memory T Cell Activation by a Novel Peptide Targeting Kv1.3 Channel in a Rat Experimental Autoimmune Encephalomyelitis Model

Li, Zhi; Liu, Wanhong; Han, Song; Peng, Biwen; Yin, Jun; Wu, Yingliang; He, Xiaohua; Li, Wenxin

doi:10.1074/jbc.m112.379594

Cited by 42 publications

(48 citation statements)

References 50 publications

(58 reference statements)

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“…Acacetin also inhibited the Ca 2+ influx and Ca 2+ -activated transcription factors NFAT1 and NF-κB p65/50. Similar to many other Kv1.3 blockers [11,12], Acacetin inhibited T cell proliferation as well as IL-2 secretion. Furthermore, siRNA knockdown of Kv1.3 channels reduced the inhibitory effect of Acacetin on IL-2 secretion.…”

Section: Discussionmentioning

confidence: 92%

“…Many studies have shown that Kv1.3 channels control Ca 2+ homeostasis by maintaining the negative membrane potential in T cells and inhibition of Kv1.3 channels significantly depolarizes the membrane potential, reducing the Ca 2+ influx [11,12,14]. Our current-clamp recordings have shown that the RMP depolarized from -41.57 ± 0.90 mV in the control to -22.35 ± 1.66 mV (n=6, P<0.001)after 7-8 min application of 30 μmol/L Acacetin.…”

Section: Resultsmentioning

confidence: 99%

“…In addition to acute inhibition of functional Kv1.3 channels, Kv1.3 blockers have been shown to produce anti-inflammatory and immunomodulatory effects through chronic reduction of the channel expression [11,12,14,27]. Before analysis, we confirmed that treatment with 10, 30 or 100 μmol/L Acacetin for up to 24 h did not result in any cytotoxicity in Jurkat cells, as assessed using both a CCK-8 kit and trypan blue dye (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…This Ca 2+ influx activates the related transcription factors NFAT and NF-κB, causing both T cell proliferation and IL-2 secretion [6,9]. Many studies, including ours, have verified that the blockade of Kv1.3 channels resulted in the reduction of Ca 2+ influx and functional inhibition of T cell activation [10,11,12,13,14], thus producing anti-inflammatory and immunomodulation effects [15,16,17,18]. Therefore, the Kv1.3 channel has become an attractive therapeutic target for inflammatory and immunological disorders [19].…”

Section: Introductionmentioning

confidence: 99%

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Acacetin Blocks Kv1.3 Channels and Inhibits Human T Cell Activation

Zhao

et al. 2014

Cell Physiol Biochem

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Backgrounds/Aims: Acacetin, a natural flavonoid compound, has been proven to exert anti-inflammatory and immunomodulatory effects. Kv1.3 channels, highly expressed in human T cells, are attractive therapeutic targets to treat inflammatory and immunological disorders. The present study was designed to characterize the inhibition of Kv1.3 channels by Acacetin in human T cells and examine its role in T cell activation. Methods: Whole-cell patch-clamp was applied to record the Kv1.3 and K_Ca currents in human T cells; Western blot was used to detect Kv1.3 expression as well as NFAT1 and NF-κB activity; Fluo-4, CCK-8 and an ELISA kit were used to measure Ca²⁺ influx, proliferation, and IL-2 secretion, respectively. Results: Acacetin decreased the Kv1.3 current, accelerated the decay rate and negatively shifted the steady-state inactivation curves in a concentration-dependent manner. The IC₅₀ values at +40 mV for peak and the current at end of pulse were 21.09 ± 2.75 and 3.63 ± 0.25 µmol/L, respectively. Treatment with Acacetin for 24 h significantly inhibited Kv1.3 protein expression. Additionally, paralleling Kv1.3 inhibition, Acacetin also inhibited Ca²⁺ influx, the Ca²⁺-activated transcription factors NFAT1, NF-κB p65/p50 activity, and proliferation as well as IL-2 production. Small interfering RNA against Kv1.3 reduced the inhibitory effect of Acacetin on IL-2 secretion. Conclusions: Acacetin blocks the Kv1.3 channel and inhibits human T cell activation. This action most likely contributes to its immunomodulatory and anti-inflammatory actions.

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Section: Discussionmentioning

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Acacetin Blocks Kv1.3 Channels and Inhibits Human T Cell Activation

Zhao

et al. 2014

Cell Physiol Biochem

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“…Kv1.3 channel is highly expressed in IL-17 + CCR7 − Th17 cells [18]. It is reported that the density of Kv1.3 channel is increased in myelin-reactive T cells from MS patients [19].…”

Section: Introductionmentioning

confidence: 99%

Kv1.3 channel blocker (ImKTx88) maintains blood–brain barrier in experimental autoimmune encephalomyelitis

et al. 2017

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BackgroundDisruption of blood–brain barrier (BBB) and subsequent infiltration of auto-reactive T lymphocytes are major characteristics of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). Kv1.3 channel blockers are demonstrated potential therapeutic effects on MS patients and EAE models, maybe via reducing activation of T cells. However, it remains to be explored whether Kv1.3 channel blockers maintain integrity of BBB in MS model.ResultsIn this study, ImKTx88, a highly selective Kv1.3 channel blocker, was used to determine the role of Kv1.3 channel in the pathogenesis of EAE, particularly in the maintenance of BBB. ImKTx88 ameliorated pathological severity in the EAE rats, and reduced extravasation into CNS. ImKTx88 also ameliorated the severity of loss or redistribution of tight junction proteins, and inhibited over-expression of ICAM-1 and VCAM-1 in the brain from EAE rats. Furthermore ImKTx88 protection was associated with activation of Ang-1/Tie-2 axis, and might be due to decreased IL-17 production.ConclusionsImKTx88 may be a novel therapeutic agent for MS treatment by stabilizing the BBB.Electronic supplementary materialThe online version of this article (doi:10.1186/s13578-017-0158-2) contains supplementary material, which is available to authorized users.

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Targeting Potassium Channels Kv1.3 and K_C_a3.1: Routes to Selective Immunomodulators in Autoimmune Disorder Treatment?

Wang

Xiang

2013

Pharmacotherapy

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The Kv1.3 and KC a 3.1 potassium channels are promising targets for the treatment of autoimmune disorders. Many Kv1.3 and KC a 3.1 blockers have a more favorable adverse event profiles than existing immunosuppressants, suggesting the selectivity of Kv1.3 and KC a 3.1 blockade. The Kv1.3 and KC a 3.1 blockers exert differential effects in different autoimmune diseases. The Kv1.3 inhibitors or gene deletion have been shown to have benefits in multiple sclerosis, type 1 diabetes, rheumatoid arthritis, psoriasis, and rapidly progressive glomerulonephritis. The KC a 3.1 blockers have demonstrated efficacy in human primary biliary cirrhosis and showed protective effects in animal models of severe colitis, allergic encephalomyelitis, inflammatory bowel disease, and multiple sclerosis. The KC a 3.1 blockers are not considered candidates for treatment of multiple sclerosis. The selective immunosuppressive effects of the Kv1.3 and KC a 3.1 blockers are due to the differences in their distribution on autoimmune-related immune cells and tissues and β1 integrin (very late activating antigen)-Kv1.3 channel cross-talk.

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Selective Inhibition of CCR7− Effector Memory T Cell Activation by a Novel Peptide Targeting Kv1.3 Channel in a Rat Experimental Autoimmune Encephalomyelitis Model

Cited by 42 publications

References 50 publications

Acacetin Blocks Kv1.3 Channels and Inhibits Human T Cell Activation

Acacetin Blocks Kv1.3 Channels and Inhibits Human T Cell Activation

Kv1.3 channel blocker (ImKTx88) maintains blood–brain barrier in experimental autoimmune encephalomyelitis

Targeting Potassium Channels Kv1.3 and K_C_a3.1: Routes to Selective Immunomodulators in Autoimmune Disorder Treatment?

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Selective Inhibition of CCR7− Effector Memory T Cell Activation by a Novel Peptide Targeting Kv1.3 Channel in a Rat Experimental Autoimmune Encephalomyelitis Model

Cited by 42 publications

References 50 publications

Acacetin Blocks Kv1.3 Channels and Inhibits Human T Cell Activation

Acacetin Blocks Kv1.3 Channels and Inhibits Human T Cell Activation

Kv1.3 channel blocker (ImKTx88) maintains blood–brain barrier in experimental autoimmune encephalomyelitis

Targeting Potassium Channels Kv1.3 and KCa3.1: Routes to Selective Immunomodulators in Autoimmune Disorder Treatment?

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Targeting Potassium Channels Kv1.3 and K_C_a3.1: Routes to Selective Immunomodulators in Autoimmune Disorder Treatment?