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首页> 外文期刊>The FASEB Journal >Cell-autonomous cytotoxicity of type I interferon response via induction of endoplasmic reticulum stress
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Cell-autonomous cytotoxicity of type I interferon response via induction of endoplasmic reticulum stress

机译：通过诱导内质网应激对 I 型干扰素反应的细胞自主细胞毒性

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The interaction of IFN with specific membrane receptors that transduce death-inducing signals is considered to be the principle mechanism of IFN-induced cytotoxicity. In this study, the classic non-cell-autonomous cytotoxicity of IFN was augmented by cell-autonomous mechanisms that operated independently of the interaction of IFN with its receptors. Cells primed to produce IFN by 5-azacytidine (5-aza) underwent endoplasmic reticulum (ER) stress. The chemical chaperones tauroursodeoxycholate (TUDCA) and 4-phenylbutyrate (4-PBA), as well as the iron chelator ciclopirox (CPX), which reduces ER stress, alleviated the cytotoxicity of 5-aza. Ablation of CCAAT-enhancer-binding protein homologous protein (CHOP), the major ER stress-associated proapoptotic transcription factor, protected fibroblasts from 5-aza only when the cytotoxicity was examined cell autonomously. In a medium transfer experiment in which the cell-autonomous effects of 5-aza was dissociated, CHOP ablation was incapable of modulating cytotoxicity; however, neutralization of IFN receptor was highly effective. Also the levels of caspase activation showed a distinct profile between the cell-autonomous and themedium-transfer experiments. We suggest that besides the classic paracrinemechanism, cell-autonomous mechanisms that involve induction of ER stress also participate. These results have implications in the development of anti-IFN-based therapies and expand the class of pathologic states that are viewed as protein-misfolding diseases.
机译：IFN与转导死亡信号的特异性膜受体的相互作用被认为是IFN诱导细胞毒性的主要机制。在这项研究中，IFN的经典非细胞自主细胞毒性被独立于IFN与其受体相互作用的细胞自主机制所增强。通过5-氮杂胞苷（5-氮杂）产生IFN的细胞经历了内质网（ER）应激。化学伴侣牛磺酸脱氧胆酸盐 （TUDCA） 和 4-苯基丁酸酯 （4-PBA） 以及降低内质网应激的铁螯合剂环吡酮 （CPX） 减轻了 5-氮杂的细胞毒性。CCAAT 增强子结合蛋白同源蛋白 （CHOP） 是主要的 ER 应激相关促凋亡转录因子，消融仅在自主检查细胞毒性时保护成纤维细胞免受 5-aza 的侵害。在解离5-aza的细胞自主作用的培养基转移实验中，CHOP消融不能调节细胞毒性;然而，IFN受体的中和作用非常有效。此外，半胱天冬酶活化水平在细胞自主和培养基转移实验之间显示出不同的特征。我们认为，除了经典的旁分泌机制外，涉及诱导内质网应激的细胞自主机制也参与其中。这些结果对基于抗IFN的疗法的开发具有重要意义，并扩大了被视为蛋白质错误折叠疾病的病理状态类别。

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