STAT4 沉默通过抑制 NF-κB 通路调节 Th1/Th2 免疫应答保护大鼠自身免疫性心肌炎。
Silencing of STAT4 Protects Against Autoimmune Myocarditis by Regulating Th1/Th2 Immune Response via Inactivation of the NF-κB Pathway in Rats.
机构信息
Department of Cardiovascular Medicine, Shanxi Dayi Hospital Affiliated to Shanxi Medical University, No. 99, Longcheng Street, Taiyuan, 030032, Shanxi Province, People's Republic of China.
Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan, 030001, People's Republic of China.
出版信息
Inflammation. 2019 Aug;42(4):1179-1189. doi: 10.1007/s10753-019-00978-3.
Signal transducer and activator of transcription 4 (STAT4) has been implicated in the progression of myocarditis. The aim of the current study was to investigate the role by which STAT4 influences autoimmune myocarditis in an attempt to identify a theoretical therapeutic perspective for the condition. After successful establishment of an autoimmune myocarditis rat model, the expression patterns of STAT4, NF-κB pathway-related genes, Th1 inflammatory cytokines (IFN-γ and IL-2), and Th2 inflammatory cytokines (IL-6 and IL-10) were subsequently determined. The rats with autoimmune myocarditis were treated with oe-STAT4 or sh-STAT4 lentiviral vectors to evaluate the role of STAT4 in autoimmune myocarditis, or administrated with 1 mL 10 μmol/L of BAY11-7082 (the NF-κB pathway inhibitor) via tail vein to investigate the effect of the NF-κB pathway on autoimmune myocarditis. Finally, cell apoptosis was evaluated. The serum levels of IFN-γ and IL-2, extent of IκBα and P65 phosphorylation, and the expression of STAT4 were elevated, while the serum levels of IL-6 and IL-10 as well as the expression of IκBα were reduced among the rats with autoimmune myocarditis, which was accompanied by an increase in the apoptotic cells. More importantly, the silencing of STAT4 or the inhibition of the NF-κB pathway was detected to result in a decrease in the serum levels of IFN-γ and IL-2 and an elevation of the serum levels of IL-6 and IL-10, and inhibited myocardial cell apoptosis in rats with autoimmune myocarditis. Moreover, STAT4 silencing was also observed to decrease the extent of IκBα and P65 phosphorylation while acting to elevate the expression of IκBα. Taken together, silencing of STAT4 could hinder the progression of autoimmune myocarditis by balancing the expression of Th1/Th2 inflammatory cytokines via the NF-κB pathway, which may provide a novel target for experimental autoimmune myocarditis (EAM) treatment.
信号转导子和转录激活子 4（STAT4）已被牵涉到心肌炎的进展中。本研究旨在探究 STAT4 影响自身免疫性心肌炎的作用机制，以期为该疾病提供一种理论治疗角度。成功建立自身免疫性心肌炎大鼠模型后，测定 STAT4、NF-κB 通路相关基因、Th1 炎性细胞因子（IFN-γ 和 IL-2）和 Th2 炎性细胞因子（IL-6 和 IL-10）的表达模式。用 oe-STAT4 或 sh-STAT4 慢病毒载体处理自身免疫性心肌炎大鼠，评估 STAT4 在自身免疫性心肌炎中的作用，或经尾静脉给予 1 mL 10 μmol/L 的 BAY11-7082（NF-κB 通路抑制剂），以研究 NF-κB 通路对自身免疫性心肌炎的影响。最后，评估细胞凋亡。结果显示，自身免疫性心肌炎大鼠的血清 IFN-γ 和 IL-2 水平、IκBα 和 P65 磷酸化程度以及 STAT4 表达升高，而血清 IL-6 和 IL-10 水平以及 IκBα 表达降低，同时伴有凋亡细胞增加。更重要的是，沉默 STAT4 或抑制 NF-κB 通路可导致自身免疫性心肌炎大鼠血清 IFN-γ 和 IL-2 水平降低，IL-6 和 IL-10 水平升高，并抑制心肌细胞凋亡。此外，还观察到 STAT4 沉默可降低 IκBα 和 P65 磷酸化程度，同时提高 IκBα 表达。综上所述，沉默 STAT4 可通过 NF-κB 通路平衡 Th1/Th2 炎性细胞因子的表达，从而阻碍自身免疫性心肌炎的进展，为实验性自身免疫性心肌炎（EAM）的治疗提供了新的靶点。
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