Department of Medicine, University of Cambridge, School of Clinical Medicine, Addenbrookes Hospital, Cambridge CB2 0QQ, United Kingdom.
Proc Natl Acad Sci U S A. 2010 Oct 12;107(41):17698-703. doi: 10.1073/pnas.1011736107. Epub 2010 Sep 27.
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.
内质网（ER）应激反应可检测细胞生理功能的故障，而微生物模式识别受体可识别传染性病原体造成的外部威胁。本研究调查了内质网应激诱导是否会影响单核细胞衍生树突状细胞中促炎细胞因子的表达。内质网应激的激活与 Toll 样受体（TLR）激动剂结合，可显著增强独特的 IL-23 p19 亚基的 mRNA 表达，并且还显著增加了 IL-23 蛋白的分泌。这些作用在 IL-12 分泌中未观察到。IL-23 基因是内质网应激诱导的转录因子 C/EBP 同源蛋白（CHOP）的靶标，在 ER 应激和 TLR 刺激的情况下，其结合增强。在 U937 细胞中敲低 CHOP 可显著降低 TLR 和 ER 应激对 IL-23p19 表达的协同作用，但不影响其他 LPS 反应基因的表达。还在生理环境中研究了内质网应激信号的整合以及 CHOP 在诱导 IL-23 反应中的作用：沙眼衣原体感染髓样细胞会导致 CHOP mRNA 的表达，并诱导 CHOP 与 IL-23 启动子结合。此外，敲低 CHOP 可显著降低针对这种胞内细菌的 IL-23 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影响先天和适应性免疫反应的性质。
