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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 NFAT1 and NF-κB p65/p50 activities.Jurkat cells were pre-treated with 0, 10, 30, or 100 μM Lovastatin for 30 min, then stimulated with PHA + PMA for 4 h. The cells received equal volume of DMSO were defined as control. (A) Representative western blotting analysis of NFAT1 and phospho-NF-κB p65/p50 activities. The summarized relative NFAT1 and phospho-NF-κB p65/p50 expression analysis from at least 3 experiments was shown in (B) (NFAT1), (C) (p65), and (D) (p50). *P < 0.05, **P < 0.01 vs. control, #P < 0.05, ##P < 0.01 and ###P < 0.001 vs. PHA + PMA stimulated group without Lovastatin.
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f7: Effect of Lovastatin on the NFAT1 and NF-κB p65/p50 activities.Jurkat cells were pre-treated with 0, 10, 30, or 100 μM Lovastatin for 30 min, then stimulated with PHA + PMA for 4 h. The cells received equal volume of DMSO were defined as control. (A) Representative western blotting analysis of NFAT1 and phospho-NF-κB p65/p50 activities. The summarized relative NFAT1 and phospho-NF-κB p65/p50 expression analysis from at least 3 experiments was shown in (B) (NFAT1), (C) (p65), and (D) (p50). *P < 0.05, **P < 0.01 vs. control, #P < 0.05, ##P < 0.01 and ###P < 0.001 vs. PHA + PMA stimulated group without Lovastatin.

Mentions: In T cells, Ca2+ influx and intracellular Ca2+ concentration elevation activate Ca2+ -dependent enzyme, and thereby Ca2+ -related transcription factors1834, so we further investigated the modulation effect of Lovastatin on NFAT1 and NF-κB p65/50. In Fig. 7, the expression of NFAT1 and phospho-NF-κBp65/50 was increased with stimulation by PHA + PMA (P < 0.01 for NFAT1 and p50, P < 0.05 for p65). Treatment with 10, 30 and 100 μM Lovastatin apparently suppressed the expression level of all these three factors concentration-dependently.


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 NFAT1 and NF-κB p65/p50 activities.Jurkat cells were pre-treated with 0, 10, 30, or 100 μM Lovastatin for 30 min, then stimulated with PHA + PMA for 4 h. The cells received equal volume of DMSO were defined as control. (A) Representative western blotting analysis of NFAT1 and phospho-NF-κB p65/p50 activities. The summarized relative NFAT1 and phospho-NF-κB p65/p50 expression analysis from at least 3 experiments was shown in (B) (NFAT1), (C) (p65), and (D) (p50). *P < 0.05, **P < 0.01 vs. control, #P < 0.05, ##P < 0.01 and ###P < 0.001 vs. PHA + PMA stimulated group without Lovastatin.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f7: Effect of Lovastatin on the NFAT1 and NF-κB p65/p50 activities.Jurkat cells were pre-treated with 0, 10, 30, or 100 μM Lovastatin for 30 min, then stimulated with PHA + PMA for 4 h. The cells received equal volume of DMSO were defined as control. (A) Representative western blotting analysis of NFAT1 and phospho-NF-κB p65/p50 activities. The summarized relative NFAT1 and phospho-NF-κB p65/p50 expression analysis from at least 3 experiments was shown in (B) (NFAT1), (C) (p65), and (D) (p50). *P < 0.05, **P < 0.01 vs. control, #P < 0.05, ##P < 0.01 and ###P < 0.001 vs. PHA + PMA stimulated group without Lovastatin.
Mentions: In T cells, Ca2+ influx and intracellular Ca2+ concentration elevation activate Ca2+ -dependent enzyme, and thereby Ca2+ -related transcription factors1834, so we further investigated the modulation effect of Lovastatin on NFAT1 and NF-κB p65/50. In Fig. 7, the expression of NFAT1 and phospho-NF-κBp65/50 was increased with stimulation by PHA + PMA (P < 0.01 for NFAT1 and p50, P < 0.05 for p65). Treatment with 10, 30 and 100 μM Lovastatin apparently suppressed the expression level of all these three factors concentration-dependently.

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