Liang Jian, Wang Jing, Azfer Asim, Song Wenjun, Tromp Gail, Kolattukudy Pappachan E, Fu Mingui
Biomolecular Science Center, College of Medicine, University of Central Florida, 4000 Central Florida Boulevard, Orlando, FL 32816, USA.
J Biol Chem. 2008 Mar 7;283(10):6337-46. doi: 10.1074/jbc.M707861200. Epub 2008 Jan 4.
Activated macrophages play an important role in many inflammatory diseases. However, the molecular mechanisms controlling macrophage activation are not completely understood. Here we report that a novel CCCH-zinc finger protein family, MCPIP1, 2, 3, and 4, encoded by four genes, Zc3h12a, Zc3h12b, Zc3h12c, and Zc3h12d, respectively, regulates macrophage activation. Northern blot analysis revealed that the expression of MCPIP1 and MCPIP3 was highly induced in macrophages in response to treatment with lipopolysaccharide (LPS). Although not affecting cell surface marker expression and phagocytotic function, overexpression of MCPIP1 significantly blunted LPS-induced inflammatory cytokine and NO(2)(.) production as well as their gene expression. Conversely, short interfering RNA-mediated reduction in MCPIP1 augmented LPS-induced inflammatory gene expression. Further studies demonstrated that MCPIP1 did not directly affect the mRNA stability of tumor necrosis factor alpha and monocyte chemoattractant protein 1 (MCP-1) but strongly inhibited LPS-induced tumor necrosis factor alpha and inducible nitric-oxide synthase promoter activation. Moreover, we found that forced expression of MCPIP1 significantly inhibited LPS-induced nuclear factor-kappaB activation. These results identify MCP-induced proteins, a novel CCCH-zinc finger protein family, as negative regulators in macrophage activation and may implicate them in host immunity and inflammatory diseases.
活化的巨噬细胞在许多炎症性疾病中起重要作用。然而，控制巨噬细胞活化的分子机制尚未完全阐明。在此我们报告，一个由四个基因Zc3h12a、Zc3h12b、Zc3h12c和Zc3h12d分别编码的新型CCCH型锌指蛋白家族，即MCPIP1、2、3和4，可调节巨噬细胞活化。Northern印迹分析显示，在用脂多糖（LPS）处理后，巨噬细胞中MCPIP1和MCPIP3的表达被高度诱导。虽然不影响细胞表面标志物的表达和吞噬功能，但MCPIP1的过表达显著减弱了LPS诱导的炎性细胞因子和NO(2)(.)的产生及其基因表达。相反，短干扰RNA介导的MCPIP1表达降低增强了LPS诱导的炎性基因表达。进一步的研究表明，MCPIP1并不直接影响肿瘤坏死因子α和单核细胞趋化蛋白1（MCP-1）的mRNA稳定性，但强烈抑制LPS诱导的肿瘤坏死因子α和诱导型一氧化氮合酶启动子的激活。此外，我们发现MCPIP1的强制表达显著抑制LPS诱导的核因子κB的激活。这些结果确定了MCP诱导蛋白，一个新型的CCCH型锌指蛋白家族，为巨噬细胞活化的负调节因子，并可能表明它们在宿主免疫和炎症性疾病中的作用。
