Chronic Calcium Channel Inhibitor Verapamil Antagonizes TNF-α-Mediated Inflammatory Reaction and Protects Against Inflammatory Arthritis in Mice
Chronic Calcium Channel Inhibitor Verapamil Antagonizes TNF-α-Mediated Inflammatory Reaction and Protects Against Inflammatory Arthritis in Mice
复制标题
慢性钙通道抑制剂维拉帕米拮抗 TNF-α 介导的炎症反应并预防小鼠炎症性关节炎
DOI：
10.1007/s10753-016-0396-1
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发表时间：
2016-10-01
期刊：
影响因子：
5.1
通讯作者：
Zhao, Yunpeng
中科院分区：
文献类型：
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作者：
Wang, Wenhan;Li, Zhong;Zhao, Yunpeng
肿瘤坏死因子-α（TNF-α）在类风湿性关节炎（RA）中起主导作用。钙通道与多种炎症性疾病密切相关。然而，慢性钙通道阻滞剂维拉帕米是否在类风湿关节炎中发挥作用仍不清楚。为了研究维拉帕米在拮抗TNF-α介导的炎症反应中的作用及其潜在机制，在存在或不存在维拉帕米的情况下，在TNF-α的刺激下培养骨髓源性巨噬细胞（BMDM）细胞。评估了炎症相关细胞因子，包括IL-1、IL-6、诱导型一氧化氮合酶2（NOS-2）和环氧合酶2（考克斯-2），维拉帕米抑制TNF-α诱导的炎症细胞因子表达。此外，建立胶原诱导的关节炎（CIA）小鼠模型，并通过关节炎的临床和组织学体征评估关节炎进展。维拉帕米治疗减轻了关节炎模型中的炎症和关节破坏。此外，在体外和小鼠关节炎模型中测定了NF-κ B信号通路的活性，并且维拉帕米在体外和小鼠模型中都抑制了TNF-α诱导的NF-κ B信号通路的活化。因此，慢性钙离子通道阻滞剂维拉帕米可能为炎症性关节炎的治疗提供新的思路，并可能成为未来治疗类风湿关节炎的潜在药物。
It is well established that the tumor necrosis factor-alpha (TNF-alpha) plays a dominant role in rheumatoid arthritis (RA). Calcium channel is recently reported to be closely associated with various inflammatory diseases. However, whether chronic calcium channel blocker verapamil plays a role in RA still remains unknown. To investigate the role of verapamil in antagonizing TNF-alpha-mediated inflammation reaction and the underlying mechanisms, bone marrow-derived macrophages (BMDM) cells were cultured with stimulation of TNF-alpha, in the presence or absence of verapamil. Inflammation-associated cytokines, including IL-1, IL-6, inducible nitric oxide synthase 2 (NOS-2), and cyclooxygenase-2 (COX-2), were assessed, and verapamil suppressed TNF-alpha-induced expression of inflammatory cytokines. Furthermore, collagen-induced arthritis (CIA) mice models were established, and arthritis progression was evaluated by clinical and histological signs of arthritis. Treatment of verapamil attenuated inflammation as well as joint destruction in arthritis models. In addition, activity of NF-kB signaling pathway was determined both in vitro and in mice arthritis models, and verapamil inhibited TNF-alpha-induced activation of NF-kB signaling both in vitro and in mice models. Collectively, chronic calcium channel blocker verapamil may shed light on treatment of inflammatory arthritis and provide a potential therapeutic instrument for RA in the future.