title: 2-(1H-Benzimidazol-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol, a benzimidazole derivative, inhibits T cell proliferation involving H+/K+-ATPase inhibition.
abstract: In this study, a benzimidazole derivative named BMT-1 is revealed as a potential immunomodulatory agent. BMT-1 inhibits the activity of H+/K+-ATPases from anti-CD3/CD28 activated T cells. Furthermore, inhibition the H+/K+-ATPases by use of BMT-1 should lead to intracellular acidification, inhibiting T cell proliferation. To explore this possibility, the effect of BMT-1 on intracellular pH changes was examined by using BCECF as a pH-dependent fluorescent dye. Interestingly, increases in the pHi were observed in activated T cells, and T cells treated with BMT-1 showed a more acidic intracellular pH. Finally, BMT-1 targeted the H+/K+-ATPases and inhibited the proliferative response of anti-CD3/CD28-stimulated T cells. A cell cycle analysis indicated that BMT-1 arrested the cell cycle progression of activated T cells from the G1 to the S phase without affecting CD25 expression or interleukin-2 (IL-2) production; treating IL-2-dependent PBMCs with BMT-1 also led to the inhibition of cell proliferation. Taken together, these findings demonstrate that BMT-1 inhibits the proliferation of T cells by interfering with H+/K+-ATPases and down-regulating intracellular pHi. This molecule may be an interesting lead compound for the development of new immunomodulatory agents.
authors.affiliation: Department of Immunology, Chengdu Medical College, Chengdu 610500, China. jinliu19871987@163.com.
authors.forename: Jin
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Immunology, Chengdu Medical College, Chengdu 610500, China. huangning3168@163.com.
authors.forename: Ning
authors.initials: N
authors.lastname: Huang
authors.affiliation: Department of Immunology, Chengdu Medical College, Chengdu 610500, China. lining6931@126.com.
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.affiliation: Department of Immunology, Chengdu Medical College, Chengdu 610500, China. liusinian123@163.com.
authors.forename: Si-Nian
authors.initials: SN
authors.lastname: Liu
authors.affiliation: Department of Immunology, Chengdu Medical College, Chengdu 610500, China. limy876@aliyun.com.
authors.forename: Min-Hui
authors.initials: MH
authors.lastname: Li
authors.affiliation: Department of Oncology, Chengdu Military General Hospital, Chengdu 610083, China. Huali99@gmail.com.
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Immunology, Chengdu Medical College, Chengdu 610500, China. luoxingyan2006@163.com.
authors.forename: Xing-Yan
authors.initials: XY
authors.lastname: Luo
authors.affiliation: Department of Immunology, Chengdu Medical College, Chengdu 610500, China. yt-wang@hotmail.com.
authors.forename: Yan-Tang
authors.initials: YT
authors.lastname: Wang
authors.affiliation: Department of Immunology, Chengdu Medical College, Chengdu 610500, China. limeiligy@gmail.com.
authors.forename: Li-Mei
authors.initials: LM
authors.lastname: Li
authors.affiliation: Department of Immunology, Chengdu Medical College, Chengdu 610500, China. qiangzou99@gmail.com.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zou
authors.affiliation: Department of Immunology, Chengdu Medical College, Chengdu 610500, China. scunn519@gmail.com.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Immunology, Chengdu Medical College, Chengdu 610500, China. yangtai.bio@gmail.com.
authors.forename: Tai
authors.initials: T
authors.lastname: Yang
mesh_terms: D001562:Benzimidazoles / Q000494:pharmacology*; D018106:CD28 Antigens / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D017506:H(+)-K(+)-Exchanging ATPase / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007155:Immunologic Factors / Q000494:pharmacology; D007376:Interleukin-2 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D054328:Proton Pump Inhibitors / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism
chemical_list: D001562:Benzimidazoles; D018106:CD28 Antigens; D017252:CD3 Complex; D007155:Immunologic Factors; D007376:Interleukin-2; D054328:Proton Pump Inhibitors; C031000:benzimidazole; D017506:H(+)-K(+)-Exchanging ATPase