Molecular mechanisms of the LPS-induced non-apoptotic ER stress-CHOP pathway
Molecular mechanisms of the LPS-induced non-apoptotic ER stress-CHOP pathway
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DOI：
10.1093/jb/mvp189
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发表时间：
2010-04-01
影响因子：
2.7
通讯作者：
Gotoh, Tomomi
中科院分区：
文献类型：
--
作者：
Nakayama, Yoichiro;Endo, Motoyoshi;Gotoh, Tomomi
C/EBP同源蛋白（CHOP）是一种内质网应激诱导的转录因子，其表达可诱导细胞凋亡。我们以前的研究表明，脂多糖（LPS）诱导的CHOP表达不诱导细胞凋亡，但激活前IL-1 β激活过程。然而，CHOP激活不同途径的机制，取决于诱导刺激的差异，仍有待澄清。目前的研究表明，LPS快速激活ER功能保护途径，但不是巨噬细胞中的PERK途径。PERK在CHOP诱导中起主要作用，其他ER应激传感器介导的途径起次要作用。与ER应激诱导剂毒胡萝卜素诱导CHOP相比，LPS诱导CHOP延迟且较弱。此外，LPS预处理或ER伴侣蛋白IgH链结合蛋白（BiP）的过表达，阻止ER应激介导的细胞凋亡。LPS加IFN-γ处理的巨噬细胞与LPS处理的细胞相比产生更大量的一氧化氮（NO）。用NO供体SNAP（S-硝基-N-乙酰基-dl-青霉胺）处理比LPS处理在更早的时期诱导CHOP。NO的消耗延缓CHOP诱导并防止LPS加IFN-γ处理的细胞中的凋亡。我们的结论是，在LPS处理的巨噬细胞中，细胞凋亡被阻止，因为ER功能保护机制在CHOP表达之前被诱导，并且CHOP的诱导水平较低。
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-1 beta 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.