https://scholars.lib.ntu.edu.tw/handle/123456789/542185
Title: | Combination of nifedipine and subtherapeutic dose of cyclosporin additively suppresses mononuclear cells activation of patients with rheumatoid arthritis and normal individuals via Ca 2+-calcineurin-nuclear factor of activated T cells pathway | Authors: | Lai N.-S. CHIA-LI YU Yin W.-Y. Yu H.-C. Huang H.-B. Tung C.-H. Lu M.-C. |
Keywords: | Calcineurin; Calcium channel blocker; Cyclosporin; Nuclear factor of activated T cells; Rheumatoid arthritis | Issue Date: | 2012 | Journal Volume: | 168 | Journal Issue: | 1 | Start page/Pages: | 78-86 | Source: | Clinical and Experimental Immunology | Abstract: | Abnormal Ca 2+-mediated signalling contributes to the pathogenesis of rheumatoid arthritis (RA). However, the potential implication of calcium channel blocker in RA remained unknown. We hypothesized that nifedipine, an L-type calcium channel blocker, combined with a calcineurin inhibitor, could suppress T cell activation via targeting different level of the Ca 2+ signalling pathway. The percentage of activated T cells and the apoptotic rate of mononuclear cells (MNCs) was measured by flow cytometry. The MNC viability, cytokine production, cytosolic Ca 2+ level and activity of the nuclear factor of activated T cells (NFAT) were measured by enzyme-linked immunosorbent assay (ELISA). The NFAT-regulated gene expression, including interleukin (IL)-2, interferon (IFN)-γ and granulocyte-macrophage colony-stimulating factor (GM-CSF), was measured by real-time polymerase chain reaction (PCR). We found that the percentage of activated T cells in anti-CD3+anti-CD28-activated MNC was higher in RA patients. High doses of nifedipine (50μM) increased MNCs apoptosis, inhibited T cell activation and decreased T helper type 2 (Th1) (IFN-γ)/Th2 (IL-10) cytokine production in both groups. The Ca 2+ influx was lower in anti-CD3+anti-CD28-activated MNC from RA patients than healthy volunteers and suppressed by nifedipine. When combined with a subtherapeutic dose (50ng/ml) of cyclosporin, 1μM nifedipine suppressed the percentage of activated T cells in both groups. Moreover, this combination suppressed more IFN-γ secretion and NFAT-regulated gene (GM-CSF and IFN-γ) expression in RA-MNCs than normal MNCs via decreasing the activity of NFATc1. In conclusion, we found that L-type Ca 2+ channel blockers and subtherapeutic doses of cyclosporin act additively to suppress the Ca 2+-calcineurin-NFAT signalling pathway, leading to inhibition of T cell activity. We propose that this combination may become a potential treatment of RA. ? 2012 The Authors. Clinical and Experimental Immunology ? 2012 British Society for Immunology. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-84863269137&doi=10.1111%2fj.1365-2249.2012.04563.x&partnerID=40&md5=c2db96882df6f383281228ec26cc646a https://scholars.lib.ntu.edu.tw/handle/123456789/542185 |
ISSN: | 0009-9104 | DOI: | 10.1111/j.1365-2249.2012.04563.x | SDG/Keyword: | calcineurin; calcium ion; CD28 antigen; CD3 antigen; cyclosporin; gamma interferon; granulocyte macrophage colony stimulating factor; interleukin 10; interleukin 2; nifedipine; transcription factor NFAT; adult; apoptosis; article; calcium signaling; calcium transport; cell activation; cell activity; cell proliferation; cell viability; clinical article; controlled study; cytokine production; cytokine release; cytosol; enzyme linked immunosorbent assay; female; flow cytometry; gene expression; human; human cell; human tissue; male; mononuclear cell; priority journal; real time polymerase chain reaction; rheumatoid arthritis; T lymphocyte activation; Th2 cell; Adult; Aged; Apoptosis; Arthritis, Rheumatoid; Calcineurin; Calcium; Calcium Channel Blockers; Cyclosporine; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Interferon-gamma; Interleukin-10; Interleukin-2; Leukocytes, Mononuclear; Lymphocyte Activation; Male; Middle Aged; NFATC Transcription Factors; Nifedipine; Real-Time Polymerase Chain Reaction; Signal Transduction; T-Lymphocytes |
Appears in Collections: | 醫學系 |
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.