IL-35介导的SOCS-6通路在肺动脉高压中的调控作用

肺动脉周围炎症是肺动脉高压（PH）最典型病理特征，但炎症如何参与PH的机制不清楚。IL-35主要由调节性T细胞（Treg）分泌，具有抑制免疫功能。注射IL-35抗体到PH小鼠，我们发现：肺动脉压更高；内皮细胞（EC）增生更剧，胞内STAT1/4磷酸化水平降低明显；高通量测序示IL-35中和后SOCS-6表达下降显著。据此，我们推测IL-35可能通过STAT1/4信号通路调节SOCS-6表达，从而抑制EC增生，延缓PH发病。为验证该假说，本研究以IL-35中和抗体PH小鼠模型、Treg过继传输实验动物模型，观察IL-35对PH的影响；用慢病毒构建SOCS-6过表达小鼠建立IL-35中和抗体PH模型，观察SOCS-6 对PH发病影响；使用STAT1/4 蛋白抑制剂处理EC，观察EC增生和SOCS-6表达改变；为验证治疗前景，将IL-35注射PH小鼠体内，观察疗效。有望从免疫炎症方向开发新疗法。

Pulmonary perivascular inflammation is the pathological hallmark of pulmonary hypertension (PH), yet the exact mechanism of how inflammation is involved in PH pathogenesis remains unclear. Interleukin 35 (IL-35) is mainly secreted by regulatory T cells (Tregs) and has immunosuppressive activity. We injected IL-35 neutralizing antibody into PH mice model and observed significantly increased pulmonary arterial pressure and endothelial cell (EC) proliferation, but significantly decreased levels of STAT1/4 phosphorylation and SOCS-6 expression level as shown by high-throughput sequencing. Accordingly, we hypothesize that IL-35 may regulate SOCS-6 through STAT1/4 pathway, thereby inhibiting EC proliferation and slowing down PH onset. To test our hypothesize, this study intends to investigate how IL-35 influences PH pathogenesis by using IL-35-neutralized PH model and Tregs adoptive transfer of experimental animals; we will use lentivirus to overexpress SOCS-6 in mice and establish an IL-35-neutralized SOCS-6 overexpression model to examine the effect of SOCS-6 on PH; we will also treat EC with STAT1/4 inhibitor to monitor EC proliferation and SOCS-6 expression alteration. In order to explore the therapeutic prospect of IL-35 in PH, we will inject IL-35 into PH mice and observe the curative effect. Hopefully we can develop a novel immune-inflammatory therapeutic strategy for PH.