Immunomodulatory effects of diclofenac in leukocytes through the targeting of Kv1.3 voltage-dependent potassium channels

Villalonga, Núria; David, Miren; Bielańska, Joanna; González, Teresa; Parra, David; Soler, Concepció; Comes, Núria; Valenzuela, Carmen; Felipe, Antônio

doi:10.1016/j.bcp.2010.05.012

Cited by 77 publications

(90 citation statements)

References 40 publications

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“…We adopted two different cell culture sorting patterns for the assay of mRNA levels (Fig. 4, A and C The effect of ADWX-1 on channel expression is similar to that reported for diclofenac, a nonsteroidal anti-inflammatory drug that inhibits Kv1.3 expression in activated T lymphocytes (40). However, diclofenac is not a specific Kv1.3 channel blocker, and the mechanism involved in its inhibition of Kv1.3 expression is unknown.…”

Section: Ccr7mentioning

confidence: 75%

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

Liu

Han

et al. 2012

Journal of Biological Chemistry

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Section: Ccr7mentioning

confidence: 75%

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

Liu

Han

et al. 2012

Journal of Biological Chemistry

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“…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%

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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“…Since NSAIDs inhibit the production of cytokines from lymphocytes [2,3,4], they are also used as immunomodulatory drugs [5,6]. However, in some situations, such as in food-dependent exercise-induced anaphylaxis (FDEIA) [7,8], salicylate and its acetyl derivative, aspirin, can stimulate chemokine release from mast cells, triggering adverse immunological reactions [9,10].…”

Section: Introductionmentioning

confidence: 99%

Amphipaths Differentially Modulate Membrane Surface Deformation in Rat Peritoneal Mast Cells During Exocytosis

Kazama

Maruyama²,

Takahashi³

et al. 2013

Cell Physiol Biochem

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Background/Aims: Salicylate and chlorpromazine exert differential effects on the chemokine release from mast cells. Since these drugs are amphiphilic and preferentially partitioned into the lipid bilayers of the plasma membranes, they would induce some morphological changes in mast cells and thus affect the process of exocytosis. Methods: Employing the standard patch-clamp whole-cell recording technique, we examined the effects of salicylate and chlorpromazine on the membrane capacitance (Cm) during exocytosis in rat peritoneal mast cells. Using confocal imaging of a water-soluble fluorescent dye, lucifer yellow, we also examined their effects on plasma membrane deformation of the cells. Results: Salicylate dramatically accelerated the GTP-γ-S-induced increase in the Cm immediately after its application, whereas chlorpromazine significantly suppressed the increase. Treatment with salicylate increased the trapping of the dye on the cell surface, while treatment with chlorpromazine completely washed it out, indicating that both drugs induced membrane surface deformation in mast cells. Conclusion: This study demonstrated for the first time that membrane amphipaths, such as salicylate and chlorpromazine, may oppositely modulate the process of exocytosis in mast cells, as detected by the changes in the Cm. The plasma membrane deformation induced by the drugs was thought to be responsible for their differential effects.

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Immunomodulatory effects of diclofenac in leukocytes through the targeting of Kv1.3 voltage-dependent potassium channels

Cited by 77 publications

References 40 publications

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

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

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

Amphipaths Differentially Modulate Membrane Surface Deformation in Rat Peritoneal Mast Cells During Exocytosis

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