Pathological roles of ER stress pathway in inflammation

内质网(ER)应激途径被各种应激激活，以保护内质网功能。然而，当应激严重时，内质网应激介导的细胞凋亡通路被激活。因此，内质网应激途径参与了多种疾病的发病机制。然而，内质网应激相关疾病的确切分子机制仍不清楚。CHOP是C/EBP家族的转录因子，参与内质网应激诱导的细胞凋亡。在本研究中，我们发现内质网应激-CHOP途径通过非凋亡途径参与了炎症的发病过程。在CHOP基因敲除小鼠中，内毒素诱导的炎症改变和IL-13活性形式的分泌受到抑制。IL-1I3在炎症的早期阶段起着至关重要的作用。我们发现，原IL-113的激活过程是CHOP依赖的。因此，我们得出结论，内质网应激-CHOP通路通过调节细胞因子的分泌来调节炎症过程。IL-1I3是以前IL-16的形式产生的，在…中更活跃，不能分泌。Pro-IL-16通过caspase-1和caspase-11的蛋白分解而被激活，然后分泌。Caspase-1在炎性细胞中以caspase-1原的形式持续表达，而caspase-11也是激活caspase-1所必需的。因此，caspase-11是IL-13激活过程中的关键分子。我们发现，caspase-11在激活的巨噬细胞中的诱导是CHOP依赖的。CHOP被认为是一种诱导细胞凋亡的分子。事实上，我们之前已经证明，CHOP缺陷细胞对内质网应激诱导的细胞凋亡具有抵抗力。然而，我们发现CHOP的诱导并不能诱导内毒素处理的巨噬细胞的凋亡。在这种情况下，CHOP通过诱导caspase-11来激活IL-13的激活过程。我们还发现，在内毒素处理的巨噬细胞中，CHOP的诱导比ER功能保护分子(如Bip)的诱导延迟。因此，我们得出结论，内毒素诱导的CHOP没有诱导细胞凋亡，因为在免疫刺激的巨噬细胞中，ER功能保护系统在CHOP表达之前就已经被激活。较少

Endoplasmic reticulum (ER) stress pathway is activated by various stresses to protect ER functions. However, when stresses are severe, ER stress-mediated apoptosis pathway is activated. Therefore, ER stress pathway is involved in the pathogenesis of various diseases. However, the precise molecular mechanisms of the ER stress-related diseases are still unknown. CHOP, a transcription factor of C/EBP family, is involved in ER stress-mediated apoptosis. In this study, we found that ER stress-CHOP pathway is involved in the pathogenesis of inflammation, through non-apoptotic pathway.LPS-induced inflammatory changes and secretion of IL-13 active form in lung were suppressed in Chop knockout mice. IL-1I3 plays crucial roles in the early stage of inflammation. We found that the pro-IL-113 activation process is CHOP-dependent. Therefore, we conclude that ER stress-CHOP pathway regulates inflammatory processes through regulation of cytokine secretion. IL-1I3 is produced as pro-IL-16, which is in … More active and cannot be secreted. Pro-IL-16 is activated by proteolysis with caspase-1 and caspase-11, and then secreted. Caspase 1 is constantly expressed as pro-caspase-1 in inflammatory cells, and caspase-11 is also needed for the activation of caspase-1. Therefore, caspase-11 is a key molecule in the process of IL-13 activation. We showed that induction of caspase-11 in activated macrophages are CHOP-dependent.CHOP has been thought as an apoptosis-inducing molecule. In fact, we previously showed that CHOP-deficient cells are resistant to ER stress-induced apoptosis. However, we found that induction of CHOP do not induce apoptosis in LPS-treated macrophages. In this condition, CHOP activates IL-13 activation process, through induction of caspase-11. We also found that induction of CHOP is delayed, compared to those of ER function-protective molecules, such as BiP, in LPS-treated macrophages. Therefore, we conclude that LPS-induced CHOP does not induce apoptosis, because ER function-protective system is already activated before CHOP expression in immuno-stimulated macrophages. Less