Xu Long, Fang He, Xu Dayuan, Wang Guangyi
Center of Burns and Trauma, Changhai Hospital, Naval Medical University, Shanghai 200433, P.R. China.
Exp Ther Med. 2020 Dec;20(6):171. doi: 10.3892/etm.2020.9301. Epub 2020 Oct 9.
Uncontrolled inflammatory cytokine production by macrophages contributes to numerous conditions, including infection, endotoxemia and sepsis. A previous study proposed that endoplasmic reticulum (ER) stress acts as an essential process in inflammatory cytokine production by macrophages. The present study used a mouse sepsis model and macrophages to demonstrate that homeodomain-interacting protein kinase 2 (HIPK2) sustained cytokine production in an ER stress-dependent manner. HIPK2 expression was upregulated in the early phase of lipopolysaccharide stimulation. HIPK2 knockdown attenuated IL-6 and TNF-α production, and p65 phosphorylation in macrophages. Furthermore, the attenuated cytokine production was abolished by the ER stress agonist tunicamycin. The activation of ER stress increased the levels of IL-6 and TNF-α, and the phosphorylation of p65, in macrophages following knockdown of HIPK2. Furthermore, HIPK2 inhibition attenuated the production of IL-6 and TNF-α and . Therefore, HIPK2 sustained inflammatory cytokine production by promoting ER stress in macrophages. Targeting HIPK2 may be a potential strategy for the management of uncontrolled inflammation in clinical settings.
巨噬细胞不受控制地产生炎性细胞因子会导致多种病症，包括感染、内毒素血症和败血症。先前的一项研究提出，内质网（ER）应激是巨噬细胞产生炎性细胞因子的一个关键过程。本研究使用小鼠败血症模型和巨噬细胞来证明，同源结构域相互作用蛋白激酶2（HIPK2）以内质网应激依赖的方式维持细胞因子的产生。在脂多糖刺激的早期阶段，HIPK2表达上调。敲低HIPK2可减弱巨噬细胞中IL-6和TNF-α的产生以及p65的磷酸化。此外，内质网应激激动剂衣霉素消除了减弱的细胞因子产生。在内质网应激激活后，敲低HIPK2的巨噬细胞中IL-6和TNF-α的水平以及p65的磷酸化增加。此外，抑制HIPK2可减弱IL-6和TNF-α的产生。因此，HIPK2通过促进巨噬细胞中的内质网应激来维持炎性细胞因子的产生。靶向HIPK2可能是临床环境中控制不受控制的炎症的一种潜在策略。
