A Novel CCCH-Zinc Finger Protein Family Regulates Proinflammatory Activation of Macrophages

Abstract

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 ␣ and monocyte chemoattractant protein 1 (MCP-1) but strongly inhibited LPS-induced tumor necrosis factor ␣ and inducible nitric-oxide synthase promoter activation. Moreover, we found that forced expression of MCPIP1 significantly inhibited LPS-induced nuclear factor-B 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.Macrophages play an important role in many inflammatory disease states, including atherosclerosis, rheumatoid arthritis, emphysema, pulmonary fibrosis, and chronic pancreatitis. In these disease settings activated macrophages elaborate a large array of cytokines, growth factors, and proteolytic enzymes that are critical for tissue damage and repair (1). Numerous extracellular inducers of macrophage activation have been identified, among the most studied of which are lipopolysaccharide (LPS) 2 and interferon ␥ (IFN␥) (2). LPS is a structurally heterogenous material contained within the cell wall of Gram-negative bacteria and is recognized by animals as a molecule correlating to infection. It binds to Toll-like receptor 4 (TLR4), triggering multiple signaling cascades including those mediated through the transcription factor NF-B and the Janus N-terminal kinase and p38 kinase pathways (3).Much attention has focused on the pro-inflammatory signaling in activated macrophages but little is known about the mechanisms that negatively control inflammation. Understanding the molecular mechanisms involved in the inflammatory processes in macrophages is essential to the development of novel drug therapies against inflammatory diseases, including atherosclerosis.Previously, we identified a novel CCCH-zinc finger-containing protein that was significantly induced by MCP-1 in human peripheral blood monocytes and thus designated as MCP-induced protein (MCPIP) (4). By searching the similar sequences in GenBank TM , we found that four members belong to this protein family, designated as MCPIP1, 2, 3, and ...

Comparison of biomarkers for systemic juvenile idiopathic arthritis

“…Of the nine genes Articles in our group that met the more stringent false discovery rate, interestingly ZC3H12B encodes a protein with a role in proinflammatory actions of macrophages (31). In addition, connective tissue growth factor (CTGF) is associated with several functions including fibrosis, angiogenesis, and tumorigenesis and is believed to play a role in inflammatory disorders including rheumatoid arthritis and CTGF polymorphisms are associated with systemic sclerosis (32)(33)(34).…”

MCP-1-induced protein-1, an immune regulator

“…2). Numerous studies show that MCPIP1 is involved in many processes, such as the promotion of angiogenesis (Niu et al, 2008), inhibition of macrophage activation (Liang et al, 2008), attenuation of myocardial dysfunction (Niu et al, 2011), and induction of cardiomyoblast death (Younce and Kolattukudy, 2010). The RNase and deubiquitinase activities of MCPIP1 are well studied, and the NCD structure is solved.…”

“…MCPIP1 is induced by MCP-1 in human peripheral blood monocytes or by IL-1β in human monocyte-derived macrophages through the activation of the NF-κB signaling pathway (Skalniak et al, 2009). MCPIP1 can also be induced by lipopolysaccharide (LPS) in mouse macrophages (Liang et al, 2008;Matsushita et al, 2009).…”

“…The substrates of MCPIP1 and their functions are summarized in Table 1. First, it is identified as a transcription factor and proved to regulate the expression of multiple genes involved in different aspects of immune response (Zhou et al, 2006;Liang et al, 2008;Niu et al, 2008). MCPIP1 negatively regulates the LPS-induced promoter activity of TNFα and iNOS (Liang et al, 2008).…”

“…First, it is identified as a transcription factor and proved to regulate the expression of multiple genes involved in different aspects of immune response (Zhou et al, 2006;Liang et al, 2008;Niu et al, 2008). MCPIP1 negatively regulates the LPS-induced promoter activity of TNFα and iNOS (Liang et al, 2008). It can also reportedly induce glial differentiation in NT2 cells by increasing GFAP expression and inducing astrocyte morphology (Vrotsos et al, 2009).…”