Trypanosoma cruzi-infected cardiomyocytes produce chemokines and cytokines that trigger potent nitric oxide-dependent trypanocidal activity
Trypanosoma cruzi-infected cardiomyocytes produce chemokines and cytokines that trigger potent nitric oxide-dependent trypanocidal activity
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DOI：
10.1161/01.cir.102.24.3003
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发表时间：
2000-12-12
期刊：
影响因子：
37.8
通讯作者：
Silva, JS
中科院分区：
文献类型：
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作者：
Machado, FS;Martins, GA;Silva, JS
背景-克氏锥虫感染小鼠心肌炎的发病机制仍然知之甚少。因此，了解触发白细胞迁移到心脏的介质以及这些可能的介质的细胞来源非常重要。在这项研究中，我们研究了（1）一氧化氮合酶（NOS）的诱导，（2）NO的合成，（3）杀锥虫活性，和（4）趋化因子和细胞因子mRNA表达的分离的心肌细胞感染克氏锥虫。方法和结果-小鼠心肌细胞分离，感染克氏锥虫，并评估诱导型NOS（iNOS）的诱导，亚硝酸盐的产生，杀锥虫活性，以及细胞因子和趋化因子mRNA表达。我们发现克氏锥虫感染的小鼠胚胎心肌细胞产生亚硝酸盐，并表达趋化因子生长相关癌基因、干扰素γ诱导的单核细胞因子、巨噬细胞炎性蛋白-2、干扰素γ诱导蛋白、RANTES和单核细胞趋化蛋白、iNOS以及细胞因子肿瘤坏死因子（TNF）-α和白细胞介素（TL）-1 β的mRNA。单独添加IL-1 β、干扰素-γ、TNF-α或单核细胞趋化蛋白、巨噬细胞炎性蛋白-2和干扰素-γ诱导蛋白到培养的心肌细胞中导致NO产生，但杀锥虫活性低。然而，同时添加IL-1 β，干扰素-γ，和TNF-α或趋化因子的文化导致诱导型一氧化氮合酶，高水平的亚硝酸盐，和显着的杀锥虫活性。iNOS/L-精氨酸途径介导后者的活动，因为它被抑制治疗与N-G-monomethyl-L-arginine. Conclusions-这些结果表明，iNOS激活和促炎细胞因子和趋化因子产生的心肌细胞可能控制寄生虫的生长和细胞流入，从而有助于在克氏锥虫感染的小鼠中看到的chagerebral心肌病的发病机制。
Background-The pathogenesis of myocarditis that occurs in Trypanosoma cruzi-infected mice is still poorly understood. Therefore, it is important to know the mediators that trigger leukocyte migration to the heart as well as the cellular source of these possible mediators. In this study, we investigated (1) NO synthase (NOS) induction, (2) NO synthesis, (3) trypanocidal activity, and (4) chemokine and cytokine mRNA expression by isolated cardiomyocytes infected with T cruzi.Methods and Results-Mouse cardiomyocytes were isolated, infected with T cruzi, and evaluated for induction of inducible NOS (iNOS), nitrite production, trypanocidal activity, and cytokine and chemokine mRNA expression. We found that T cruzi-infected murine embryonic cardiomyocytes produced nitrite and expressed mRNAs for the chemokines chemokine growth-related oncogene, monokine induced by interferon-gamma, macrophage inflammatory protein-2, interferon-gamma -inducible protein, RANTES, and monocyte chemotactic protein, for iNOS, and for the cytokines tumor necrosis factor (TNF)-alpha and interleukin (TL)-1 beta. Separate addition of IL-1 beta, interferon-gamma, TNF-alpha or monocyte chemotactic protein, macrophage inflammatory protein-2, and interferon-gamma -inducible protein, to cultured cardiomyocytes resulted in NO production but low trypanocidal activity. However, simultaneous addition of IL-1 beta, interferon-gamma, and TNF-alpha or the chemokines to cultures resulted in the induction of iNOS, high levels of nitrite, and a marked trypanocidal activity. The iNOS/L-arginine pathway mediated the latter activity, inasmuch as it was inhibited by treatment with N-G-monomethyl-L-arginine.Conclusions-These results indicate that iNOS activation and the proinflammatory cytokines and chemokines produced by cardiomyocytes are likely to control parasite growth and cell influx, thus contributing to the pathogenesis of chagasic cardiomyopathy seen in T cruzi-infected mice.