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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

Block effect of Lovastatin on KCa currents in human T cells.KCa currents were elicited by 200 ms voltage-ramp from −120 to + 40 mV at the holding potential of −40 mV. The currents slope conductance was acquired by fitting the curves between −120 and −40 mV with linear equation. (A) Representative current-voltage relationship traces recorded in the absence or presence of 30 μM Lovastatin in Jurkat cells. (B) Summarized slope conductance data from 5 Jurkat cells. (C) Representative current-voltage traces of KCa channel obtained from PBTCs. (D) Summarized slope conductance from 5 PBTCs. (E) Representative superimposed current-voltage relationships traces from a Jurkat cell recorded in K+ Ringer solution with or without 30 μM Lovastatin. (F) Summarized data from 5 Jurkat cells. N.S. represented no statistical significance. Data are expressed as the mean ± SEM.
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f4: Block effect of Lovastatin on KCa currents in human T cells.KCa currents were elicited by 200 ms voltage-ramp from −120 to + 40 mV at the holding potential of −40 mV. The currents slope conductance was acquired by fitting the curves between −120 and −40 mV with linear equation. (A) Representative current-voltage relationship traces recorded in the absence or presence of 30 μM Lovastatin in Jurkat cells. (B) Summarized slope conductance data from 5 Jurkat cells. (C) Representative current-voltage traces of KCa channel obtained from PBTCs. (D) Summarized slope conductance from 5 PBTCs. (E) Representative superimposed current-voltage relationships traces from a Jurkat cell recorded in K+ Ringer solution with or without 30 μM Lovastatin. (F) Summarized data from 5 Jurkat cells. N.S. represented no statistical significance. Data are expressed as the mean ± SEM.

Mentions: Next, we observed the block effect of Lovastatin on KCa channel both in Jurkat T cells and PBTCs, because KCa2.2 is the main KCa channel expressed in Jurkat T cells30, whereas KCa3.1 is the main KCa channel involved in PBTCs17. KCa current was elicited by a 200 ms ramp pulse ranging from −120 mV to + 40 mV at the holding potential of −40 mV. The representative current traces were shown in Fig. 4A,C,E. To avoid the mixture of outward Kv currents, the slope conductance between −120 and −40 mV was measured by fitting the curve with linear equation. As shown in Fig. 4B,D, 30 μM Lovastatin did not block KCa currents in both Jurkat cells and PBTCs in normal Ringer’s solution. In Jurkat cells, the slope conductance was 0.61 ± 0.05 nS at control, and 0.65 ± 0.05 nS with Lovastatin application (n = 5, P > 0.05). In PBTCs, he slope conductance was 0.90 ± 0.14 nS at control, and 0.91 ± 0.12 nS with Lovastatin application (n = 5, P > 0.05). In Fig. 4E,F, to increase their slope conductance, the KCa currents were recorded in K+ Ringer’s solution, and similarly, 30 μM Lovastatin exerted no block effect on KCa channel (1.48 ± 0.19 vs. 1.48 ± 0.22 nS, P > 0.05). Consequently, our results suggested that Lovastatin had no apparent block effect on KCa channel in human T cells.


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)

Block effect of Lovastatin on KCa currents in human T cells.KCa currents were elicited by 200 ms voltage-ramp from −120 to + 40 mV at the holding potential of −40 mV. The currents slope conductance was acquired by fitting the curves between −120 and −40 mV with linear equation. (A) Representative current-voltage relationship traces recorded in the absence or presence of 30 μM Lovastatin in Jurkat cells. (B) Summarized slope conductance data from 5 Jurkat cells. (C) Representative current-voltage traces of KCa channel obtained from PBTCs. (D) Summarized slope conductance from 5 PBTCs. (E) Representative superimposed current-voltage relationships traces from a Jurkat cell recorded in K+ Ringer solution with or without 30 μM Lovastatin. (F) Summarized data from 5 Jurkat cells. N.S. represented no statistical significance. Data are expressed as the mean ± SEM.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f4: Block effect of Lovastatin on KCa currents in human T cells.KCa currents were elicited by 200 ms voltage-ramp from −120 to + 40 mV at the holding potential of −40 mV. The currents slope conductance was acquired by fitting the curves between −120 and −40 mV with linear equation. (A) Representative current-voltage relationship traces recorded in the absence or presence of 30 μM Lovastatin in Jurkat cells. (B) Summarized slope conductance data from 5 Jurkat cells. (C) Representative current-voltage traces of KCa channel obtained from PBTCs. (D) Summarized slope conductance from 5 PBTCs. (E) Representative superimposed current-voltage relationships traces from a Jurkat cell recorded in K+ Ringer solution with or without 30 μM Lovastatin. (F) Summarized data from 5 Jurkat cells. N.S. represented no statistical significance. Data are expressed as the mean ± SEM.
Mentions: Next, we observed the block effect of Lovastatin on KCa channel both in Jurkat T cells and PBTCs, because KCa2.2 is the main KCa channel expressed in Jurkat T cells30, whereas KCa3.1 is the main KCa channel involved in PBTCs17. KCa current was elicited by a 200 ms ramp pulse ranging from −120 mV to + 40 mV at the holding potential of −40 mV. The representative current traces were shown in Fig. 4A,C,E. To avoid the mixture of outward Kv currents, the slope conductance between −120 and −40 mV was measured by fitting the curve with linear equation. As shown in Fig. 4B,D, 30 μM Lovastatin did not block KCa currents in both Jurkat cells and PBTCs in normal Ringer’s solution. In Jurkat cells, the slope conductance was 0.61 ± 0.05 nS at control, and 0.65 ± 0.05 nS with Lovastatin application (n = 5, P > 0.05). In PBTCs, he slope conductance was 0.90 ± 0.14 nS at control, and 0.91 ± 0.12 nS with Lovastatin application (n = 5, P > 0.05). In Fig. 4E,F, to increase their slope conductance, the KCa currents were recorded in K+ Ringer’s solution, and similarly, 30 μM Lovastatin exerted no block effect on KCa channel (1.48 ± 0.19 vs. 1.48 ± 0.22 nS, P > 0.05). Consequently, our results suggested that Lovastatin had no apparent block effect on KCa channel in human T cells.

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