Endoplasmic reticulum heat shock protein gp96/grp94 is a pro-oncogenic chaperone, not a tumor suppressor.
Endoplasmic reticulum heat shock protein gp96/grp94 is a pro-oncogenic chaperone, not a tumor suppressor.
复制标题
内质网热休克蛋白 gp96/grp94 是一种促癌伴侣，而不是肿瘤抑制因子。
DOI：
10.1002/hep.27400
复制
发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Li,Zihai
中科院分区：
文献类型：
--
作者：
Rachidi,Saleh;Sun,Shaoli;Li,Zihai
我们感谢邹博士及其同事对我们最近的文章的评论。我们文章的主要信息是交感神经系统（SNS）保护肝脏免受急性损伤。这一结论是基于有证据表明，减少儿茶酚胺神经递质可减少肝祖细胞（HPC）的积累，并加重对乙酰氨基酚（APAP）引起的肝损伤，而外源性儿茶酚胺异丙肾上腺素（ISO）可逆转这些作用。我们首先发现，缺乏儿茶酚胺的多巴胺b-羟化酶缺失小鼠中HPC的数量减少，并证明这种HPC消耗被ISO逆转（图1A）。在培养的603B细胞中进行的研究表明，ISO的作用可能是通过直接作用于HPCs介导的（而不是间接通过ISO介导的肝损伤加重）。ISO在体外促进祖细胞生长（图1D），这种作用被b-肾上腺素能受体拮抗剂普萘洛尔（PRL；图1E）所抑制。在野生型小鼠中，通过丙氨酸转氨酶（ALT）和肝脏组织学评估，单用ISO不会造成肝损伤（图3A， B）。同样，ISO也没有增强apap诱导的肝损伤。相反，ISO显著减轻了apap处理小鼠的肝损伤，提高了小鼠的存活率（图3C， D）。这些改善的结果与iso相关的HPC数量增加平行（图3E）。相反，肾上腺素受体拮抗剂PRL明显加重了apap诱导的肝损伤（图3F）。在APAP之前对对照小鼠进行交感神经切除术也严重加重了APAP诱导的肝损伤，平均ALT约为15,000 IU/L（支持图2）。
We thank Dr. Zou and colleagues for their comment on our recent article. 1 The main message of our article was that the sympathetic nervous system (SNS) protects the liver from acute injury. This conclusion was based on evidence that decreasing cathecholamine neurotransmitters reduced hepatic progenitor cell (HPC) accumulation and exacerbated liver injury caused by acetaminophen (APAP), whereas exogenous administration of the cathecholamine, isoproterenol (ISO), reversed these effects. We first showed that the number of HPCs was reduced in dopamine b-hydroxylase null mice, which lack cathecholamines, and demonstrated that this HPC depletion was reversed by ISO (Fig. 1A). That the effect of ISO was likely mediated by direct actions on HPCs (and not indirectly by ISO-mediated exacerbation of liver injury) was then shown by studies in cultured 603B cells. ISO increased progenitor cell growth in vitro (Fig. 1D), and this effect was inhibited by the b-adrenoceptor antagonist, propranolol (PRL; Fig. 1E). In wildtype mice, ISO alone caused no liver injury, as assessed by alanine transaminase (ALT) and liver histology (Fig. 3A, B). Similarly, ISO did not enhance APAP-induced liver injury. Rather, ISO markedly reduced liver injury and improved survival of APAP-treated mice (Fig. 3C, D). These improved outcomes paralleled ISO-related increases in HPC numbers (Fig. 3E). In contrast, the badrenoceptor antagonist, PRL, clearly worsened APAP-induced liver injury (Fig. 3F). Performing sympathectomies in control mice before APAP also profoundly worsened APAP-induced liver injury, such that the mean ALT was approximately 15,000 IU/L (Supporting Fig. 2).