Trypanosoma cruzi, the causative agent of Chagas disease, modulates interleukin-6-induced STAT3 phosphorylation via gp130 cleavage in different host cells
Trypanosoma cruzi, the causative agent of Chagas disease, modulates interleukin-6-induced STAT3 phosphorylation via gp130 cleavage in different host cells
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DOI：
10.1016/j.bbadis.2012.12.003
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发表时间：
2013-03-01
影响因子：
6.2
通讯作者：
Pilar Aoki, Maria
中科院分区：
文献类型：
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作者：
Eric Ponce, Nicolas;Antonio Carrera-Silva, Eugenio;Pilar Aoki, Maria
白细胞介素-6主要通过糖蛋白gp 130激活转录因子STAT 3介导宿主防御和细胞存活，糖蛋白gp 130是几种IL-6型细胞因子的共享信号转导受体。我们已经报道了心肌寄生虫克氏锥虫保护小鼠心肌细胞免于凋亡。在协议中，强烈诱导的抗凋亡因子Bcl-2被发现在心脏纤维在感染的急性期，建立一个更高的阈值对细胞凋亡。我们在这里报告，无活性cruzipain，主要的半胱氨酸蛋白酶分泌的寄生虫，特异性触发TLR 2和随后释放的IL-6，这作为一个重要的抗凋亡因子的心肌细胞培养。尽管在活性cruzipain刺激下发现了可比的IL-6水平，但饥饿的心肌细胞单层不能从凋亡中获救。此外，用活性cruzipain处理的心肌细胞完全废除了重组IL-6诱导的STAT 3磷酸化和核转位。在脾细胞上也观察到这种抑制，但当该酶与寄生虫半胱氨酸蛋白酶抑制剂chagasin复合时，这种抑制被逆转。此外，IL-6诱导的p-STAT 3的抑制在用来自锥虫的预活化上清液刺激的脾细胞中得到证实。为了解释这些观察结果，我们发现cruzipain酶促裂解重组gp 130胞外域，并诱导释放膜远端N-末端结构域的人外周血单核细胞上的这种受体。这些结果首次表明，寄生虫可以通过调节其半胱氨酸蛋白酶活性来改变IL-6诱导的反应，这表明特异性抑制剂可能有助于改善免疫细胞活化和心脏保护作用。(C)2012 Elsevier B. V.保留所有权利。
Interleukin-6 mediates host defense and cell survival mainly through the activation of the transcription factor STAT3 via the glycoprotein gp130, a shared signal-transducing receptor for several IL-6-type cytokines. We have reported that the cardiotrophic parasite Tlypanosoma cruzi protects murine cardiomyocytes from apoptosis. In agreement, an intense induction of the anti-apoptotic factor Bcl-2 is found in cardiac fibers during the acute phase of infection, establishing a higher threshold against apoptosis. We report here that inactive cruzipain, the main cysteine protease secreted by the parasite, specifically triggered TLR2 and the subsequent release of IL-6, which acted as an essential anti-apoptotic factor for cardiomyocyte cultures. Although comparable IL-6 levels were found under active cruzipain stimulation, starved cardiac cell monolayers could not be rescued from apoptosis. Moreover, cardiomyocytes treated with active cruzipain completely abrogated the STAT3 phosphorylation and nuclear translocation induced by recombinant IL-6. This inhibition was also observed on splenocytes, but it was reverted when the enzyme was complexed with chagasin, a parasite cysteine protease inhibitor. Furthermore, the inhibition of IL-6-induced p-STAT3 was evidenced in spleen cells stimulated with pre-activated supernatants derived from trypomastigotes. To account for these observations, we found that cruzipain enzymatically cleaved recombinant gp130 ectodomain, and induced the release of membrane-distal N-terminal domain of this receptor on human peripheral blood mononuclear cells. These results demonstrate, for the first time, that the parasite may modify the IL-6-induced response through the modulation of its cysteine protease activity, suggesting that specific inhibitors may help to improve the immune cell activation and cardioprotective effects. (C) 2012 Elsevier B.V. All rights reserved.