title: 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 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.
authors.affiliation: Research Center of Ion Channelopathy, Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Zhao
authors.affiliation: Research Center of Ion Channelopathy, Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Dong
authors.affiliation: Research Center of Ion Channelopathy, Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Qian
authors.affiliation: Institute of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
authors.forename: Sen
authors.initials: S
authors.lastname: Li
authors.affiliation: Research Center of Ion Channelopathy, Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
authors.forename: Qiong-Feng
authors.initials: QF
authors.lastname: Wu
authors.affiliation: Research Center of Ion Channelopathy, Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Ding
authors.affiliation: Research Center of Ion Channelopathy, Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Research Center of Ion Channelopathy, Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
authors.forename: Bin-Bin
authors.initials: BB
authors.lastname: Wang
authors.affiliation: Department of anesthesiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
authors.forename: Ke-fang
authors.initials: KF
authors.lastname: Guo
authors.affiliation: Research Center of Ion Channelopathy, Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
authors.forename: Jiang-jiao
authors.initials: JJ
authors.lastname: Xie
authors.affiliation: Research Center of Ion Channelopathy, Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Research Center of Ion Channelopathy, Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
authors.forename: Yu-Hua
authors.initials: YH
authors.lastname: Liao
authors.affiliation: Research Center of Ion Channelopathy, Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
authors.forename: Yi-Mei
authors.initials: YM
authors.lastname: Du
mesh_terms: D002118:Calcium / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D056747:Immunomodulation / Q000187:drug effects; D007376:Interleukin-2 / Q000378:metabolism; D019169:Jurkat Cells; D051664:Kv1.3 Potassium Channel / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism; D008148:Lovastatin / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*
chemical_list: D007376:Interleukin-2; D051664:Kv1.3 Potassium Channel; D051036:Large-Conductance Calcium-Activated Potassium Channels; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D026902:Potassium Channel Blockers; D008148:Lovastatin; D002118:Calcium