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 in vitro. Importantly, MCPIP-1 markedly downregulated the production of ROS, MPO, and proinflammatory cytokines (e.g., interleukin-1β, interleukin-6, tumor necrosis factor-α, interleukin-8, and interferon-γ) 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.

中文翻译：

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单核细胞趋化蛋白 1 诱导蛋白 1 在炎症性肠病中高表达并负向调节中性粒细胞活性


单核细胞趋化蛋白 1 诱导蛋白 1 (MCPIP-1) 在激活的免疫细胞中高表达，在负向调节免疫反应中发挥重要作用。然而，其在炎症性肠病（IBD）发病机制中调节中性粒细胞功能的作用仍不清楚。在这里，我们发现与健康对照相比，IBD患者发炎粘膜的MCPIP-1在转录和翻译水平上均显着增加，主要在中性粒细胞中表达。有趣的是，MG-132（一种减少MCPIP-1降解的蛋白酶体抑制剂）进一步促进中性粒细胞在体外表达MCPIP-1。重要的是，MCPIP-1 显着下调 ROS、MPO 和促炎细胞因子（例如，白细胞介素 1 β 、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 IBD 的迁移中性粒细胞。一致地，在骨髓靶向过度表达 MCPIP-1 的小鼠的中性粒细胞中观察到与 MG-132 相同的功能变化。总而言之，这些发现表明 MCPIP-1 通过抑制 ROS、MPO 和促炎细胞因子的产生并抑制迁移，在调节中性粒细胞活性中发挥负面作用。 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的治疗提供一种治疗方法。