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 Ca2+ 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.
Highlights
Lovastatin is a member of Statins, which are beneficial in a lot of immunologic cardiovascular diseases and T cell-mediated autoimmune diseases
Different concentrations of Lovastatin ranging from 1 to 100 μ M were applied to block the Kv1.3 channel in Jurkat cells
Our research demonstrated that Lovastatin blocked Kv1.3 channel in a concentration- and voltage-dependent manner, accelerated the decay rate of current curve and negatively shifted the steady-state inactivation curve without significant effect on KCa channels
Summary
Lovastatin is a member of Statins, which are beneficial in a lot of immunologic cardiovascular diseases and T cell-mediated autoimmune diseases. Many reports suggested that Statins inhibited T cell activation by blocking the Mevalonate pathway and reducing the isoprenoid metabolites[9,13,14]. Blocking Kv1.3 channel can inhibit the Ca2+ influx and Ca2+ -mediated signal pathway, and exert inhibitory effects on T cell activation[19,20,21,22]. In many autoimmune animal models such as multiple sclerosis, rheumatoid arthritis, Type I diabetes, the pathogenic TEM (effector memory T) cells were reported to significantly up-regulate Kv1.3 channel expression after activation, Kv1.3 blockers can selectively inhibit TEM cells and alleviate the immunologic damage[16,23,24,25,26]. Our research demonstrated for the first time that Lovastatin can block Kv1.3 channel, decrease Ca2+ influx and Ca2+ -activated transcriptional factors, and inhibit the activation, proliferation of human T cells. We may conclude that Lovastatin exerts immunomodulatory effect through Kv1.3 channel
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