Department of Gastroenterology, The Shanghai Tenth People's Hospital of Tongji University, Shanghai, China.
Department of Gastroenterology, Affiliated Hospital of Putian University, Putian, China.
Mediators Inflamm. 2020 Dec 22;2020:8812020. doi: 10.1155/2020/8812020. eCollection 2020.
Monocyte chemotactic protein 1-induced protein 1 (MCPIP-1) is highly expressed in activated immune cells and plays an important role in negatively regulating immune responses. However, its role in regulating neutrophil functions in the pathogenesis of inflammatory bowel disease (IBD) is still unclear. Here, we found that MCPIP-1 was markedly increased at both the transcriptional and translational levels in inflamed mucosa of IBD patients compared with healthy controls, which was mainly expressed in neutrophils. Interestingly, MG-132, a proteasome inhibitor reducing the degradation of MCPIP-1, further facilitated neutrophils to express MCPIP-1 . Importantly, MCPIP-1 markedly downregulated the production of ROS, MPO, and proinflammatory cytokines (e.g., interleukin-1, interleukin-6, tumor necrosis factor-, interleukin-8, and interferon-) and suppressed the migration of IBD neutrophils. Consistently, the same functional changes were observed in neutrophils from mice with myeloid-targeted overexpression of MCPIP-1 as MG-132 did. Altogether, these findings suggest that MCPIP-1 plays a negative role in regulating neutrophil activities through suppressing the production of ROS, MPO, and proinflammatory cytokines and inhibiting the migration. MG-132 may partially modulate the function of neutrophils via the induction of MCPIP-1. Therefore, targeting MCPIP-1 or exogenous supplementation of MG-132 may provide a therapeutic approach in the treatment of IBD.
单核细胞趋化蛋白 1 诱导蛋白 1（MCPIP-1）在活化的免疫细胞中高度表达，在负向调控免疫应答中发挥重要作用。然而，其在调节炎症性肠病（IBD）中性粒细胞功能中的作用尚不清楚。在这里，我们发现与健康对照者相比，IBD 患者炎症黏膜中 MCPIP-1 的转录和翻译水平均显著增加，主要在中性粒细胞中表达。有趣的是，蛋白酶体抑制剂 MG-132 降低了 MCPIP-1 的降解，进一步促进了中性粒细胞表达 MCPIP-1。重要的是，MCPIP-1 显著下调了 ROS、MPO 和促炎细胞因子（如白细胞介素-1、白细胞介素-6、肿瘤坏死因子-α、白细胞介素-8 和干扰素-γ）的产生，并抑制了 IBD 中性粒细胞的迁移。一致地，在骨髓细胞中过表达 MCPIP-1 的小鼠中性粒细胞中观察到了与 MG-132 相同的功能变化。总之，这些发现表明，MCPIP-1 通过抑制 ROS、MPO 和促炎细胞因子的产生以及抑制迁移，在调节中性粒细胞活性中发挥负向作用。MG-132 可能通过诱导 MCPIP-1 部分调节中性粒细胞的功能。因此，靶向 MCPIP-1 或外源性补充 MG-132 可能为 IBD 的治疗提供一种方法。
