Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Honjo 1-1-1, Japan.
J Biochem. 2010 Apr;147(4):471-83. doi: 10.1093/jb/mvp189. Epub 2009 Nov 16.
The expression of C/EBP homologous protein (CHOP), which is an endoplasmic reticulum (ER) stress-induced transcription factor, induces apoptosis. Our previous study demonstrated that lipopolysaccharide (LPS)-induced CHOP expression does not induce apoptosis, but activates a pro-IL-1beta activation process. However, the mechanism by which CHOP activates different pathways, depending on the difference in the inducing stimuli, remains to be clarified. The present study shows that LPS rapidly activates the ER function-protective pathway, but not the PERK pathway in macrophages. PERK plays a major role in CHOP induction, and other ER stress sensors-mediated pathways play minor roles. The induction of CHOP by LPS was delayed and weak, in comparison with CHOP induction by ER stress-inducer thapsigargin. In addition, LPS-pre-treatment or overexpression of ER chaperone, IgH chain binding protein (BiP), prevented ER stress-mediated apoptosis. LPS plus IFN-gamma-treated macrophages produce a larger amount of nitric oxide (NO) in comparison with LPS-treated cells. Treatment with the NO donor, SNAP (S-nitro-N-acetyl-dl-penicillamine), induces CHOP at an earlier period than LPS treatment. The depletion of NO retards CHOP induction and prevents apoptosis in LPS plus IFN-gamma-treated cells. We concluded that apoptosis is prevented in LPS-treated macrophages, because the ER function-protective mechanisms are induced before CHOP expression, and induction level of CHOP is low.
C/EBP 同源蛋白（CHOP）的表达是内质网（ER）应激诱导的转录因子，可诱导细胞凋亡。我们之前的研究表明，脂多糖（LPS）诱导的 CHOP 表达不会诱导细胞凋亡，而是激活了前白细胞介素 1β（IL-1β）的激活过程。然而，CHOP 根据诱导刺激的不同激活不同途径的机制仍有待阐明。本研究表明，LPS 可迅速激活巨噬细胞中的 ER 功能保护途径，但不能激活 PERK 途径。PERK 在 CHOP 诱导中起主要作用，而其他 ER 应激传感器介导的途径则起次要作用。与 ER 应激诱导剂 thapsigargin 诱导的 CHOP 相比，LPS 诱导的 CHOP 诱导时间延迟且较弱。此外，LPS 预处理或 ER 伴侣 IgH 链结合蛋白（BiP）过表达可防止 ER 应激介导的细胞凋亡。与 LPS 处理的细胞相比，LPS 加 IFN-γ处理的巨噬细胞产生的一氧化氮（NO）量更大。用 NO 供体 SNAP（S-亚硝基-N-乙酰-DL-青霉胺）处理可使 CHOP 在比 LPS 处理更早的时期诱导。NO 的消耗会延迟 CHOP 的诱导并防止 LPS 加 IFN-γ处理的细胞凋亡。我们得出的结论是，LPS 处理的巨噬细胞中发生了细胞凋亡的预防，因为在 CHOP 表达之前诱导了 ER 功能保护机制，并且 CHOP 的诱导水平较低。
