Pim-1信号在炎症性肠病发病机制中的免疫调节作用研究

炎症性肠病（IBD）的发病与肠粘膜免疫紊乱有关，但是相关信号分子如何调节免疫细胞功能目前还不清楚。我们前期实验中发现Pim-1信号参与小鼠结肠炎炎症的启动，并且与免疫细胞功能状态有关，阻断Pim-1信号可以抑制肠道炎症反应，根据这一结果我们提出假设：Pim-1信号参与IBD肠粘膜固有免疫和适应性免疫功能的调节。本课题以研究巨噬细胞、na?veT细胞激活过程中Pim-1表达调控的信号分子为切入点，进一步研究Pim-1在巨噬细胞激活、Th1/Th2、Treg/Th17免疫平衡调节方面的作用及机制，同时利用IBD模型，探讨体内抑制Pim-1信号对肠道异常免疫反应的影响及机制。本项目从分子、细胞、动物多方面来探讨Pim-1信号对IBD肠粘膜固有及适应性免疫细胞功能的调节作用，以阐明Pim-1信号参与肠道异常免疫反应的机制，旨在为IBD的治疗提供新的靶点，为利用Pim-1信号治疗IBD打下理论基础。

Inflammatory bowel disease (IBD) is characterized by chronic relapsing inflammatory disorders of the gastrointestinal tract. Although the etiology of IBD remains unclear, accumulating evidence has indicated that dysfunction of the mucosal immune system plays an important role in the pathogenesis of IBD，Pim-1 is a serine/threonine kinase that is crucially involved in the control of cell growth, differentiation and apoptosis. Accumulating data support that Pim-1 are essential components of an endogenous pathway that regulates T cell growth and survival. The crucial role of Pim kinase in immune cells activation and proliferation makes it an attractive target for immunomodulatory therapy. Indeed, the pharmacological inhibition of Pim kinases exhibits immunomodulatory benefits, However, it remains unclear whether pim-1 kinase is involved in the pathology of IBD and whether pim-1 kinase could modulate T help cell differentiation and macrophage activation during the development of IBD. .The aims of this study were to explore the role of Pim-1 kinase in the pathology of IBD and to assess whether Pim-1 kinase may act to regulate innate and adaptive immune responses,inhibiting Pim-1 kinase may be of therapeutic benefit as a treatment regimen for IBD. In vitro effects of Pim-1 on LPS-induced macrophage activation and Th cell differentiation,as well as in vivo effects of PIM-Inhibitor (PIM-Inh) in mice with TNBS or DSS-induced colitis, were explored. In acute colitis, daily PIM-Inh treatment commenced 2 days after TNBS delivery, while in relapsing colitis PIM-Inh treatment commenced after three weekly TNBS or DSS administrations. Colon inflammation, production of proinflammatory cytokines and NF-κB activation in colon tissues,and Th1/Th2,Th17/Treg cell populations in lamina propria mononuclear cells (LPMCs) and mesenteric lymph node cells (MLNs) were assayed..In summary, our data may provide evidence that Pim-1 may act as a central regulator in the immune response by regulates macrophages activation and Th cells differentiation.These findings may offer a promising alternative to our current approaches of managing IBD.