A CCR1 antagonist prevents the development of experimental autoimmune myocarditis in association with T cell inactivation
A CCR1 antagonist prevents the development of experimental autoimmune myocarditis in association with T cell inactivation
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DOI：
10.1016/j.yjmcc.2006.03.432
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发表时间：
2006-06-01
影响因子：
5
通讯作者：
Isobe, Mitsuaki
中科院分区：
文献类型：
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作者：
Futamatsu, Hideki;Suzuki, Jun-ichi;Isobe, Mitsuaki
趋化因子在诱导免疫细胞趋化中起着重要作用。CCR1是一种趋化因子受体，表达于中性粒细胞、单核细胞和T淋巴细胞上。CCR1在免疫中的作用尚未得到很好的研究。我们证明了CCR1在T淋巴细胞上的作用以及CCR1拮抗剂BX471在心肌炎中的作用。Lewis大鼠第0天用心肌肌球蛋白免疫建立实验性自身免疫性心肌炎模型。然后每天皮下注射BX471(BX0组：n=7)或从第14天开始(BX14组：n=7)，于第21天处死。免疫组织化学和流式细胞仪分析证实CCR1在心肌细胞中有表达。BX0组心肌炎发展几乎完全阻止，BX14组心肌炎病变面积明显缩小。心功能明显改善。核糖核酸酶保护实验显示，CCR1拮抗剂处理可抑制心脏IL-6、IL-1和TNF-α的mRNA表达。用心肌肌球蛋白免疫的对照大鼠分离的CD4阳性T细胞进行抗原特异性T细胞增殖试验。CCR1拮抗剂可抑制T细胞增殖。此外，我们通过Western印迹显示，CCR1拮抗剂抑制了肌球蛋白刺激的T细胞ERK1/2和JNK活性，而IL-2逆转了这种抑制。CCR1拮抗剂通过抑制细胞因子的表达和诱导T细胞失活来减轻EAM的严重程度。因此，CCR1拮抗剂可能为心肌炎的治疗提供新的治疗策略。(C)2006 Elsevier Inc.保留所有权利。
Chemokines play an important role in induction of chemotaxis of immune cells. CCR1 is a chemokine receptor expressed on neutrophils, monocytes, and T lymphocytes. The role of CCR1 in immunity is not well examined. We demonstrated the role of CCR1 on T lymphocytes and the effect of a CCR1 antagonist, BX471 in myocarditis. Lewis rats were immunized with cardiac myosin on day 0 to establish experimental autoimmune myocarditis. Rats were then administered BX471 subcutaneously every day (group BX0: n = 7) or from day 14 (group BX14: n = 7) and were killed on day 21. We confirmed expression of CCR1 in cells infiltrating the myocardium by immunohistochemistry and FACS analysis. The development of myocarditis was almost completely prevented in group BX0, and myocarditis-affected areas were significantly decreased in size in group BX14. Cardiac function was markedly improved. Ribonuclease protection assay showed that the CCR1 antagonist treatment suppressed mRNA expression for IL-6, IL-1, and TNF-alpha in the hearts. An antigen-specific T cell proliferation assay was performed with CD4-positive T cells isolated from control rats immunized with cardiac myosin. T cell proliferation was inhibited by the CCR1 antagonist. Additionally, we showed by Western blot that the CCR1 antagonist suppressed ERK1/2 and JNK activities in T cells stimulated with myosin and that IL-2 reversed this suppression. The CCR1 antagonist reduced the severity of EAM by inhibiting cytokine expression and inducing T cell inactivation. Thus, the CCR1 antagonist may provide a novel therapeutic strategy treatment of myocarditis. (c) 2006 Elsevier Inc. All rights reserved.