Endoplasmic reticulum stress-induced transcription factor, CHOP, is crucial for dendritic cell IL-23 expression
Endoplasmic reticulum stress-induced transcription factor, CHOP, is crucial for dendritic cell IL-23 expression
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DOI：
10.1073/pnas.1011736107
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发表时间：
2010-10-12
影响因子：
11.1
通讯作者：
Gaston, J. S. Hill
中科院分区：
文献类型：
--
作者：
Goodall, Jane C.;Wu, Changxin;Gaston, J. S. Hill
内质网（ER）应激反应检测细胞生理功能障碍，微生物模式识别受体识别感染因子造成的外部威胁。本研究调查了是否单核细胞来源的树突状细胞的促炎细胞因子的表达受到ER应激诱导。ER应激的激活，与Toll样受体（TLR）激动剂相结合，显着增强IL-23的独特的p19亚基的mRNA的表达，也显着增加IL-23蛋白的分泌。对于IL-12分泌没有观察到这些作用。IL-23基因被发现是ER应激诱导的转录因子C/EBP同源蛋白（CHOP）的靶点，其在ER应激和TLR刺激的背景下表现出增强的结合。在U937细胞中敲低CHOP显著降低TLR和ER应激对IL-23 p19表达的协同作用，但不影响其他LPS应答基因的表达。ER应激信号的整合和在诱导IL-23应答中对CHOP的需求也在生理环境中进行了研究：用沙眼衣原体感染骨髓细胞导致CHOP mRNA的表达，并诱导CHOP与IL-23启动子的结合。此外，敲低CHOP显著降低了IL-23响应于该细胞内细菌的表达。因此，病原体和其他环境因素对ER应激的影响可以深刻地影响先天性和适应性免疫应答的性质。
The endoplasmic reticulum(ER) stress response detects malfunctions in cellular physiology, and microbial pattern recognition receptors recognize external threats posed by infectious agents. This study has investigated whether proinflammatory cytokine expression by monocyte-derived dendritic cells is affected by the induction of ER stress. Activation of ER stress, in combination with Toll-like receptor (TLR) agonists, markedly enhanced expression of mRNA of the unique p19 subunit of IL-23, and also significantly augmented secretion of IL-23 protein. These effects were not seen for IL-12 secretion. The IL-23 gene was found to be a target of the ER stress-induced transcription factor C/EBP homologous protein (CHOP), which exhibited enhanced binding in the context of both ER stress and TLR stimulation. Knockdown of CHOP in U937 cells significantly reduced the synergistic effects of TLR and ER stress on IL-23p19 expression, but did not affect expression of other LPS-responsive genes. The integration of ER stress signals and the requirement for CHOP in the induction of IL-23 responses was also investigated in a physiological setting: infection of myeloid cells with Chlamydia trachomatis resulted in the expression of CHOP mRNA and induced the binding of CHOP to the IL-23 promoter. Furthermore, knockdown of CHOP significantly reduced the expression of IL-23 in response to this intracellular bacterium. Therefore, the effects of pathogens and other environmental factors on ER stress can profoundly affect the nature of innate and adaptive immune responses.