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Lovastatin blocks Kv1.3 channel in human T cells: a new mechanism to explain its immunomodulatory properties.

Zhao N, Dong Q, Qian C, Li S, Wu QF, Ding D, Li J, Wang BB, Guo KF, Xie JJ, Cheng X, Liao YH, Du YM - Sci Rep (2015)

Bottom Line: However, 30 μM Lovastatin had no apparent effect on KCa current in human T cells.At last, Mevalonate application only partially reversed the inhibition of Lovastatin on IL-2 secretion, and the siRNA against Kv1.3 also partially reduced this inhibitory effect of Lovastatin.In conclusion, Lovastatin can exert immunodulatory properties through the new mechanism of blocking Kv1.3 channel.

View Article: PubMed Central - PubMed

Affiliation: Research Center of Ion Channelopathy, Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.

ABSTRACT
Lovastatin is a member of Statins, which are beneficial in a lot of immunologic cardiovascular diseases and T cell-mediated autoimmune diseases. Kv1.3 channel plays important roles in the activation and proliferation of T cells, and have become attractive target for immune-related disorders. The present study was designed to examine the block effect of Lovastatin on Kv1.3 channel in human T cells, and to clarify its new immunomodulatory mechanism. We found that Lovastatin inhibited Kv1.3 currents in a concentration- and voltage-dependent manner, and the IC50 for peak, end of the pulse was 39.81 ± 5.11, 6.92 ± 0.95 μM, respectively. Lovastatin also accelerated the decay rate of current inactivation and negatively shifted the steady-state inactivation curves concentration-dependently, without affecting the activation curve. However, 30 μM Lovastatin had no apparent effect on KCa current in human T cells. Furthermore, Lovastatin inhibited Ca(2+) influx, T cell proliferation as well as IL-2 production. The activities of NFAT1 and NF-κB p65/50 were down-regulated by Lovastatin, too. At last, Mevalonate application only partially reversed the inhibition of Lovastatin on IL-2 secretion, and the siRNA against Kv1.3 also partially reduced this inhibitory effect of Lovastatin. In conclusion, Lovastatin can exert immunodulatory properties through the new mechanism of blocking Kv1.3 channel.

No MeSH data available.


Related in: MedlinePlus

Effect of Lovastatin on the Ca2+ influx to Ca2+ -depleted Jurkat cells.Jurkat cells were loaded with fluo-4 AM and re-suspended in the Ca2+ -free Ringer solution. Then, 10, 30 or 100 μM Lovastatin was applied into the extracellular solution. After 30 min incubation, intracellular Ca2+ release and Ca2+ influx were elicited by 1 μM TG and 2 mM CaCl2, respectively. (A) The summarized time course of ΔF/F0 value was shown for the cells treated with 0 or 10, 30, 100 μM Lovastatin. (B) The summarized ΔF/F0 value of the peak intracellular Ca2+ release response induced by TG. *P < 0.05 vs. control. (C) The summarized ΔF/F0 value of the maximum Ca2+ influx response after 2 mM CaCl2 application. **P < 0.01 and ***P < 0.001 vs. control. All the data are expressed as mean ± SEM from at least 5 replicate experiments.
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f6: Effect of Lovastatin on the Ca2+ influx to Ca2+ -depleted Jurkat cells.Jurkat cells were loaded with fluo-4 AM and re-suspended in the Ca2+ -free Ringer solution. Then, 10, 30 or 100 μM Lovastatin was applied into the extracellular solution. After 30 min incubation, intracellular Ca2+ release and Ca2+ influx were elicited by 1 μM TG and 2 mM CaCl2, respectively. (A) The summarized time course of ΔF/F0 value was shown for the cells treated with 0 or 10, 30, 100 μM Lovastatin. (B) The summarized ΔF/F0 value of the peak intracellular Ca2+ release response induced by TG. *P < 0.05 vs. control. (C) The summarized ΔF/F0 value of the maximum Ca2+ influx response after 2 mM CaCl2 application. **P < 0.01 and ***P < 0.001 vs. control. All the data are expressed as mean ± SEM from at least 5 replicate experiments.

Mentions: Many previous studies have shown that Kv1.3 channel plays a vital role in the Ca2+ homeostasis of T cells through maintaining the negative membrane potential, and blockade of Kv1.3 channel significantly reduces Ca2+ influx193133. As shown in Fig. 6A, in Ca2+ -free Ringer’s solution, 1 μM TG caused a small increase of the intracellular Ca2+ concentration. After 2 mM CaCl2 application, Ca2+ flowed into Jurkat cells through CRAC channel and induced significant intracellular Ca2+ increase. Incubation with 10 and 30 μM Lovastatin did not alter the Ca2+ release induced by TG, but 100 μM Lovastatin slightly inhibited this reaction (P < 0.05, Fig. 6B). In Fig. 6C, 10, 30 and 100 μM Lovastatin concentration-dependently inhibited the Ca2+ influx by 25.36% (P < 0.01), 39.29% (P < 0.001) and 64.29% (P < 0.001), respectively.


Lovastatin blocks Kv1.3 channel in human T cells: a new mechanism to explain its immunomodulatory properties.

Zhao N, Dong Q, Qian C, Li S, Wu QF, Ding D, Li J, Wang BB, Guo KF, Xie JJ, Cheng X, Liao YH, Du YM - Sci Rep (2015)

Effect of Lovastatin on the Ca2+ influx to Ca2+ -depleted Jurkat cells.Jurkat cells were loaded with fluo-4 AM and re-suspended in the Ca2+ -free Ringer solution. Then, 10, 30 or 100 μM Lovastatin was applied into the extracellular solution. After 30 min incubation, intracellular Ca2+ release and Ca2+ influx were elicited by 1 μM TG and 2 mM CaCl2, respectively. (A) The summarized time course of ΔF/F0 value was shown for the cells treated with 0 or 10, 30, 100 μM Lovastatin. (B) The summarized ΔF/F0 value of the peak intracellular Ca2+ release response induced by TG. *P < 0.05 vs. control. (C) The summarized ΔF/F0 value of the maximum Ca2+ influx response after 2 mM CaCl2 application. **P < 0.01 and ***P < 0.001 vs. control. All the data are expressed as mean ± SEM from at least 5 replicate experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4663632&req=5

f6: Effect of Lovastatin on the Ca2+ influx to Ca2+ -depleted Jurkat cells.Jurkat cells were loaded with fluo-4 AM and re-suspended in the Ca2+ -free Ringer solution. Then, 10, 30 or 100 μM Lovastatin was applied into the extracellular solution. After 30 min incubation, intracellular Ca2+ release and Ca2+ influx were elicited by 1 μM TG and 2 mM CaCl2, respectively. (A) The summarized time course of ΔF/F0 value was shown for the cells treated with 0 or 10, 30, 100 μM Lovastatin. (B) The summarized ΔF/F0 value of the peak intracellular Ca2+ release response induced by TG. *P < 0.05 vs. control. (C) The summarized ΔF/F0 value of the maximum Ca2+ influx response after 2 mM CaCl2 application. **P < 0.01 and ***P < 0.001 vs. control. All the data are expressed as mean ± SEM from at least 5 replicate experiments.
Mentions: Many previous studies have shown that Kv1.3 channel plays a vital role in the Ca2+ homeostasis of T cells through maintaining the negative membrane potential, and blockade of Kv1.3 channel significantly reduces Ca2+ influx193133. As shown in Fig. 6A, in Ca2+ -free Ringer’s solution, 1 μM TG caused a small increase of the intracellular Ca2+ concentration. After 2 mM CaCl2 application, Ca2+ flowed into Jurkat cells through CRAC channel and induced significant intracellular Ca2+ increase. Incubation with 10 and 30 μM Lovastatin did not alter the Ca2+ release induced by TG, but 100 μM Lovastatin slightly inhibited this reaction (P < 0.05, Fig. 6B). In Fig. 6C, 10, 30 and 100 μM Lovastatin concentration-dependently inhibited the Ca2+ influx by 25.36% (P < 0.01), 39.29% (P < 0.001) and 64.29% (P < 0.001), respectively.

Bottom Line: However, 30 μM Lovastatin had no apparent effect on KCa current in human T cells.At last, Mevalonate application only partially reversed the inhibition of Lovastatin on IL-2 secretion, and the siRNA against Kv1.3 also partially reduced this inhibitory effect of Lovastatin.In conclusion, Lovastatin can exert immunodulatory properties through the new mechanism of blocking Kv1.3 channel.

View Article: PubMed Central - PubMed

Affiliation: Research Center of Ion Channelopathy, Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.

ABSTRACT
Lovastatin is a member of Statins, which are beneficial in a lot of immunologic cardiovascular diseases and T cell-mediated autoimmune diseases. Kv1.3 channel plays important roles in the activation and proliferation of T cells, and have become attractive target for immune-related disorders. The present study was designed to examine the block effect of Lovastatin on Kv1.3 channel in human T cells, and to clarify its new immunomodulatory mechanism. We found that Lovastatin inhibited Kv1.3 currents in a concentration- and voltage-dependent manner, and the IC50 for peak, end of the pulse was 39.81 ± 5.11, 6.92 ± 0.95 μM, respectively. Lovastatin also accelerated the decay rate of current inactivation and negatively shifted the steady-state inactivation curves concentration-dependently, without affecting the activation curve. However, 30 μM Lovastatin had no apparent effect on KCa current in human T cells. Furthermore, Lovastatin inhibited Ca(2+) influx, T cell proliferation as well as IL-2 production. The activities of NFAT1 and NF-κB p65/50 were down-regulated by Lovastatin, too. At last, Mevalonate application only partially reversed the inhibition of Lovastatin on IL-2 secretion, and the siRNA against Kv1.3 also partially reduced this inhibitory effect of Lovastatin. In conclusion, Lovastatin can exert immunodulatory properties through the new mechanism of blocking Kv1.3 channel.

No MeSH data available.


Related in: MedlinePlus