Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, People's Republic of China.
Dig Dis Sci. 2012 Jul;57(7):1822-31. doi: 10.1007/s10620-012-2106-7. Epub 2012 Apr 1.
Pim-1 kinase is involved in the control of cell growth, differentiation and apoptosis. Recent evidence suggests that Pim kinases play a role in immune regulation and inflammation. However, the role of Pim-1 kinase in inflammatory bowel diseases (IBD) remains unclear.
The aims of this study were to explore the role of Pim-1 kinase in the pathology of IBD and to assess whether inhibiting Pim-1 kinase may be of therapeutic benefit as a treatment regimen for IBD.
Colitic mouse model was established by the induction of dextran sodium sulfate. The expression of Pim-1 in the colonic samples of control and colitic mice was examined. Furthermore, the mice were treated with Pim-1inhibitor (PIM-Inh), then the body weight and colon inflammation were evaluated, and the production of cytokines including IFN-γ, IL-4, TGF-β and IL-17 in colon tissues was determined by ELISA. The expression of T cell master transcription factors T-bet, ROR-γt, GATA-3 and Foxp3 and Nuclear factor κB (NF-κB) and inducible nitric oxide synthase in colon tissues was detected by real-time PCR and western blot. Finally, the effect of LPS on Pim-1 expression and the effects of PIM-Inh on LPS-induced upregualtion of p65 and TNF-α in RAW264.7 cells were examined by real-time PCR and western blot.
Pim-1 expression was correlated with the degree of mucosal inflammation in vivo, and it was significantly induced by LPS in vitro. PIM-Inh had protective effects on acute colitis in vivo. Mechanistically, PIM-Inh reduced the proinflammatory immune response through the inhibition of the overactivation of macrophages and the down-regulation of excessive Th1- and Th17-type immune responses. Furthermore, PIM-Inh could skew T cell differentiation towards a Treg phenotype.
Pim-1 kinase is involved in mucosal injury/inflammation and Pim-1 kinase inhibitor may provide a novel therapeutic approach for IBD.
Pim-1 激酶参与细胞生长、分化和凋亡的调控。最近的证据表明，Pim 激酶在免疫调节和炎症中发挥作用。然而，Pim-1 激酶在炎症性肠病（IBD）中的作用尚不清楚。
本研究旨在探讨 Pim-1 激酶在 IBD 发病机制中的作用，并评估抑制 Pim-1 激酶是否可能成为治疗 IBD 的一种治疗方案。
通过诱导葡聚糖硫酸钠建立结肠炎小鼠模型。检测对照组和结肠炎小鼠结肠组织中 Pim-1 的表达。此外，用 Pim-1 抑制剂（PIM-Inh）处理小鼠，然后评估体重和结肠炎症，并通过 ELISA 测定结肠组织中细胞因子 IFN-γ、IL-4、TGF-β 和 IL-17 的产生。通过实时 PCR 和 Western blot 检测结肠组织中 T 细胞主转录因子 T-bet、ROR-γt、GATA-3 和 Foxp3 以及核因子 κB（NF-κB）和诱导型一氧化氮合酶的表达。最后，通过实时 PCR 和 Western blot 检测 LPS 对 Pim-1 表达的影响以及 PIM-Inh 对 LPS 诱导 RAW264.7 细胞中 p65 和 TNF-α 上调的影响。
Pim-1 的表达与体内黏膜炎症程度相关，体外也明显受 LPS 诱导。PIM-Inh 对体内急性结肠炎具有保护作用。机制上，PIM-Inh 通过抑制巨噬细胞过度激活和下调过度的 Th1 和 Th17 型免疫反应，减轻促炎免疫反应。此外，PIM-Inh 可使 T 细胞分化向 Treg 表型倾斜。
Pim-1 激酶参与黏膜损伤/炎症，Pim-1 激酶抑制剂可能为 IBD 提供一种新的治疗方法。
