miR-155调控Th1、Th17细胞免疫应答在早期重症急性胰腺炎发病中的作用和机制

The main reason for early mortality in patients with severe acute pancreatitis (SAP) is the systemic inflammatory response leading to multiple organ failure. The role of immune responses in the acute pancreatitis (AP) has been widespread concerned, the exact molecular mechanism is not clear. It has been reported that a large number of pro-inflammatory cytokines TNF-a and IL-17a related to Th1 and Th17 were generated in the AP and SAP, whose levels were associated with the severity of disease. MIR-155, closely related to Th17 cells, participates in the pancreas disease procedure through regulating T cell differentiation and intervening inflammatory processes. We have found that miR-155 is markedly increased in peripheral blood of AP patients and facilitates Th1 and Th17 mediated immune responses. Thus, miR-155 is supposed to be involved in the development of inflammation in AP and SAP. We will study the expression of miR-155 in peripheral blood and the pancreas from AP patients and mice. We will also investigate the potential role of miR-155 in regulating T cell immune responses in AP, MSAP and SAP and try to find the potential target genes of miR-155. Experimental AP and immunodeficiency AP models will be established and treated through blockage of miR-155 in vivo to determine whether it could prevent inflammation. This study will clarify the potential role of miR-155 in the pathogenesis of SAP, and may provide insight into the development of novel therapeutic agent for SAP.

重症急性胰腺炎（SAP）患者早期死亡的主因为全身炎症反应导致多脏器功能衰竭，其中免疫异常已受关注，确切机制不明。研究发现AP时产生大量Th1、 Th17相关促炎因子TNF-ɑ、IL-17A，其水平与疾病严重程度相关。miR-155 与Th17细胞关系密切，通过影响T细胞分化干预炎症进程，参与正常胰腺、胰腺炎继而过度到胰腺癌的多步骤进展过程。我们前期发现AP患者外周血miR-155表达升高，并促使Th1和Th17细胞效应应答，据此提出miR-155可能参与AP、SAP炎症发生过程。本课题着重研究miR-155在AP中表达和对CD4+ T细胞的免疫调节效应，寻找miR-155靶基因，阐明其在AP过程中免疫调节作用。建立野生及免疫缺陷AP、MSAP、SAP小鼠模型，靶向阻断miR-155效应应答，观察AP发展变化。本研究的完成将进一步阐明SAP发病机制，为治疗提供新思路。

重症急性胰腺炎（SAP）患者早期死亡的主因为全身炎症反应导致多脏器功能衰竭，其中免疫异常已受关注，确切机制不明。研究发现AP时产生大量Th1、 Th17相关促炎因子TNF-ɑ、IL-17A，其水平与疾病严重程度相关。miR-155 与Th17细胞关系密切，通过影响T细胞分化干预炎症进程，参与正常胰腺、胰腺炎继而过度到胰腺癌的多步骤进展过程。我们前期发现AP患者外周血miR-155表达升高，并促使Th1和Th17细胞效应应答，据此提出miR-155可能参与AP、SAP炎症发生过程。本课题着重研究miR-155在AP中表达和对CD4+ T细胞的免疫调节效应，寻找miR-155靶基因，阐明其在AP过程中免疫调节作用。建立野生及免疫缺陷AP、MSAP、SAP小鼠模型，靶向阻断miR-155效应应答，观察AP发展变化。结果证实1)Mir-155在急性胰腺炎患者外周血中显著表达，且随着病患严重而增加。2)Mir-155能够促进CD4+T细胞向Th17细胞分化和细胞炎症因子的表达，且后者在胰腺炎的炎症反应中具有重要促进作用。3)SOCS1是mir-155的直接靶基因，能够显著抑制SOCS1的表达。4)SOCS1对细胞炎症因子的抑制是通过STAT信号通路活化引起的。5)Mir-155/SOCS1/STAT1通路对急性胰腺炎的发展具有重要作用。本研究将进一步阐明SAP发病机制，为治疗提供新思路。