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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 Kv1.3 expression in Jurkat cells.(A) Jurkat cells were incubated with 10, 30, and 100 μM Lovastatin for 24 h. Then, the relative Kv1.3 mRNA expression level normalized to GAPDH was measured by real-time PCR. The summarized data from 3 replicates was shown. (B) Representative Western blotting analysis of Kv1.3 protein expression under control and after 24 h treatment with 10, 30, or 100 μM Lovastatin. (C) The summarized data from 3 replicates which were normalized to the protein expression of GAPDH. All the data was expressed as the mean ± SEM.
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f5: Effect of Lovastatin on Kv1.3 expression in Jurkat cells.(A) Jurkat cells were incubated with 10, 30, and 100 μM Lovastatin for 24 h. Then, the relative Kv1.3 mRNA expression level normalized to GAPDH was measured by real-time PCR. The summarized data from 3 replicates was shown. (B) Representative Western blotting analysis of Kv1.3 protein expression under control and after 24 h treatment with 10, 30, or 100 μM Lovastatin. (C) The summarized data from 3 replicates which were normalized to the protein expression of GAPDH. All the data was expressed as the mean ± SEM.

Mentions: Besides the acute inhibition of functional Kv1.3 channel, Kv1.3 blockers may exert anti-inflammatory effect through the down-regulation of channel expression19203132. To evaluate the effect of Lovastatin on Kv1.3 expression, Jurkat cells were incubated with 10, 30 and 100 μM Lovastatin for 24 h, and then collected to investigate the Kv1.3 mRNA and protein expression. In Fig. 5A, Lovastatin up to 100 μM performed no apparent effect on Kv1.3 mRNA expression. Similarly, the Kv1.3 protein expression was not changed, either (P > 0.05, Fig. 5).


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 Kv1.3 expression in Jurkat cells.(A) Jurkat cells were incubated with 10, 30, and 100 μM Lovastatin for 24 h. Then, the relative Kv1.3 mRNA expression level normalized to GAPDH was measured by real-time PCR. The summarized data from 3 replicates was shown. (B) Representative Western blotting analysis of Kv1.3 protein expression under control and after 24 h treatment with 10, 30, or 100 μM Lovastatin. (C) The summarized data from 3 replicates which were normalized to the protein expression of GAPDH. All the data was expressed as the mean ± SEM.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f5: Effect of Lovastatin on Kv1.3 expression in Jurkat cells.(A) Jurkat cells were incubated with 10, 30, and 100 μM Lovastatin for 24 h. Then, the relative Kv1.3 mRNA expression level normalized to GAPDH was measured by real-time PCR. The summarized data from 3 replicates was shown. (B) Representative Western blotting analysis of Kv1.3 protein expression under control and after 24 h treatment with 10, 30, or 100 μM Lovastatin. (C) The summarized data from 3 replicates which were normalized to the protein expression of GAPDH. All the data was expressed as the mean ± SEM.
Mentions: Besides the acute inhibition of functional Kv1.3 channel, Kv1.3 blockers may exert anti-inflammatory effect through the down-regulation of channel expression19203132. To evaluate the effect of Lovastatin on Kv1.3 expression, Jurkat cells were incubated with 10, 30 and 100 μM Lovastatin for 24 h, and then collected to investigate the Kv1.3 mRNA and protein expression. In Fig. 5A, Lovastatin up to 100 μM performed no apparent effect on Kv1.3 mRNA expression. Similarly, the Kv1.3 protein expression was not changed, either (P > 0.05, Fig. 5).

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