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

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.

Immune modulatory effects of statins

“…In vitro studies showed that lovastatin inhibited T‐cell proliferation, Ca 2+ influx and interleukin‐2 (IL‐2) production in T cells. Additionally recent data indicate that lovastatin blocks the Kv1.3 channel in human T cells, which presents a novel mechanism for the immunomodulatory properties of statins . Besides these direct cellular effects on signalling via blockade of GTPase isoprenylation, statins impact gene expression of pro‐inflammatory genes in the innate and adaptive immune systems and also in non‐haematopoietic cells, including endothelial cells and fibroblasts.…”

“…Additionally recent data indicate that lovastatin blocks the Kv1.3 channel in human T cells, which presents a novel mechanism for the immunomodulatory properties of statins. 8 Besides these direct cellular effects on signalling via blockade of GTPase isoprenylation, statins impact gene expression of pro-inflammatory genes in the innate and adaptive immune systems and also in non-haematopoietic cells, including endothelial cells and fibroblasts. An important novel observation is that statins also impact the immune system through effects on immune cell metabolism.…”

The effect of high-dose lovastatin therapy on patients with acute cerebral infarction

“…Lovastatin is a kind of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, which catalyzes the conversion of HMG-CoA to L-Mevalonate, leading to the blockade of cholesterol biosynthesis [17]. Statins would also inhibit the biosynthesis of isoprenoid intermediates such as geranyl and farnesyl pyrophosphate, and then affect the posttranslational prenylation of several important cell-signaling proteins during immune responses [18,19].…”

High concentrations of atorvastatin reducein-vitrofunction of conventional T and regulatory T cells

“…Natural and synthetic statins reduce the level of cellular activation as determined by the expression of CD69 and CD25 molecules, the proliferation of conventional T cells (T cons ) and cell cycle arrest [9][10][11][12][13][14]. Contradictory results regarding the effect of statins on the production of interferon (IFN)-γ, tumour necrosis factor (TNF)-α, interleukin (IL)-2, IL-4 and IL-5 by T cons have been associated with the type of statins, incubation time in culture and/or the pre-existing inflammatory condition in which they were evaluated [10][11][12][13][14]. Moreover, it is unclear if statins can modify early events downstream of T cell receptor (TCR) activation, such as calcium (Ca 2+ ) mobilization [9,13].…”