Seko Yoshinori, Kayagaki Nobuhiko, Seino Ken-ichiro, Yagita Hideo, Okumura Ko, Nagai Ryozo
Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
J Am Coll Cardiol. 2002 Apr 17;39(8):1399-403. doi: 10.1016/s0735-1097(02)01776-x.
This study was designed to investigate the roles of Fas/FasL pathway in myocardial damage in murine acute myocarditis caused by Coxsackie virus B3 (CVB3).
Cardiac myocyte apoptosis rarely occurs in murine acute myocarditis caused by CVB3. Fas/FasL belong to the tumor necrosis factor receptor/ligand superfamily of costimulatory molecules and are known to play a critical role in the induction of apoptosis, as well as in the cytotoxicty mediated by T-cells and natural killer cells.
We first analyzed the expression of Fas on cardiac myocytes in vivo and in vitro. Second, we examined the development of myocardial damage, in C3H/He mice treated with an anti-FasL monoclonal antibody (mAb), and in C3H/He-lpr/lpr mice and C3H/He-gld/gld mice infected with CVB3. Third, to investigate the effects of anti-FasL mAb treatment on the activation of the infiltrating cells, we examined the expression of interferon (IFN)-gamma and interleukin (IL)-2 as activation markers in the heart of mice by semiquantitative polymerase chain reaction.
Fas was markedly induced on cardiac myocytes with acute myocarditis. Myocardial inflammation was decreased in mice treated with anti-Fas L mAb, C3H/He-lpr/lpr mice and C3H/He-gld/gld mice. Anti-FasL mAb-treatment also decreased the expression of IFN-gamma, IL-2, inducible nitric oxide synthase and CVB3 genomes in myocardial tissue.
Our findings strongly suggested that the Fas/FasL pathway played a critical role in the development of massive myocardial necrosis through activation of infiltrating cells, and raise the possibility of immunotherapy by blocking the Fas/FasL pathway to prevent myocardial damage and improve the prognosis of patients with viral myocarditis.
本研究旨在探讨Fas/FasL通路在柯萨奇病毒B3（CVB3）所致小鼠急性心肌炎心肌损伤中的作用。
在CVB3所致小鼠急性心肌炎中，心肌细胞凋亡很少发生。Fas/FasL属于共刺激分子的肿瘤坏死因子受体/配体超家族，已知在诱导凋亡以及T细胞和自然杀伤细胞介导的细胞毒性中起关键作用。
我们首先分析了体内和体外心肌细胞上Fas的表达。其次，我们检测了用抗FasL单克隆抗体（mAb）处理的C3H/He小鼠以及感染CVB3的C3H/He-lpr/lpr小鼠和C3H/He-gld/gld小鼠中心肌损伤的发展情况。第三，为了研究抗FasL mAb处理对浸润细胞活化的影响，我们通过半定量聚合酶链反应检测了小鼠心脏中作为活化标志物的干扰素（IFN）-γ和白细胞介素（IL）-2的表达。
急性心肌炎时心肌细胞上Fas明显诱导表达。抗FasL mAb处理的小鼠、C3H/He-lpr/lpr小鼠和C3H/He-gld/gld小鼠的心肌炎症减轻。抗FasL mAb处理还降低了心肌组织中IFN-γ、IL-2、诱导型一氧化氮合酶和CVB3基因组的表达。
我们的研究结果强烈表明，Fas/FasL通路通过激活浸润细胞在大规模心肌坏死的发展中起关键作用，并增加了通过阻断Fas/FasL通路进行免疫治疗以预防心肌损伤和改善病毒性心肌炎患者预后的可能性。
