DDX家族分子DHX9负向调控IL-6效应信号的作用和机制研究

Inflammatory cytokine IL-6 effector signaling and downstream activation of STAT3 play important roles in the initiation and progression of inflammation. The regulatory mechanism of IL-6 effector signaling is an important scientific question in the research of innate immunity. DDX family members play important roles in the regulation of inflammation, and we found that DDX46 could negatively regulate inflammatory cytokines and interferon production, which was published in Nature Immunology 2017 (IF: 21.5). However, the roles of DDX family members in the regulation of IL-6 effector signaling remain unknown up to now. Here, we used siRNA library functional screening to knockdown the expression of DDX family members, and found that DHX9 knockdown significantly promoted IL-6-induced downstream STAT3 phosphorylation and activation. Moreover, we have constructed DHX9 knockout mouse and determined that DHX9 deficiency promoted IL-6 effector signaling in vivo. Hence, we intend to investigate the negative regulatory roles of DHX9 in the regulation of IL-6 effector signaling, especially STAT3 phosphorylation and activation. Moreover, we intend to investigate the roles of DHX9 in the liver inflammatory mouse disease models, so as to suggest new mechanisms and therapeutic targets for liver inflammation.

炎症因子IL-6激活其下游效应信号并介导STAT3磷酸化活化是炎症启动中的关键环节，IL-6效应通路的分子调控机制是其中重要的科学问题。DDX家族分子在炎症调控中发挥重要作用，申请人前期发现DDX46能够负向调控炎症因子和干扰素表达，以共同第一作者于2017年发表于Nature Immunology（IF：21.5）。但是，DDX家族分子在炎症因子如IL-6等效应信号通路中的调控作用目前未知。据此，我们采用干扰RNA功能性筛选策略逐一敲减DDX家族分子表达，发现敲减DHX9后IL-6激活下游效应信号及STAT3磷酸化活化显著增强。此外，在DHX9敲除小鼠中IL-6效应信号活化亦显著增强。由此，本工作拟探求DHX9抑制IL-6效应信号尤其是STAT3磷酸化活化的作用和机制，并结合肝脏炎症小鼠模型，探求DHX9调控肝脏炎症疾病进展的作用及干预靶点价值，以期为肝脏炎症提出调控新机制和干预新思路。

我们研究发现，DDX家族分子DDX58，能够通过负向调控炎症因子IL-6效应信号通路的活化，进而抑制肝脏炎症，及其介导的肝脏炎癌转化和肿瘤发生。此外，肝癌祖细胞中的DDX家族分子DDX58的表达降低，介导了其对炎症因子IL-6的反应性增强，进而促进了其向成熟肝癌的进展，本工作项目负责人以末位通讯作者，于2022年发表于Journal of Hematology & Oncology（IF：23.1）。我们同时发现，小G蛋白GaS能够通过增强肝脏炎症因子IL-6效应，进而促进肝脏炎症和炎癌转化，本工作项目负责人以末位通讯作者，于2022年发表于Hepatology（IF：17.4）。此外，我们还发现肝脏富集表达的miR-199，能够通过抑制肝细胞凋亡，进而抑制肝脏炎症和炎癌转化，本工作项目负责人以末位通讯作者，于2020年发表于Oncogenesis（IF：6.1）。