A novel CCCH-zinc finger protein family regulates proinflammatory activation of macrophages.
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.
Liang
Jian
J
Biomolecular Science Center, College of Medicine, University of Central Florida, 4000 Central Florida Boulevard, Orlando, FL 32816, USA.
Wang
Jing
J
Azfer
Asim
A
Song
Wenjun
W
Tromp
Gail
G
Kolattukudy
Pappachan E
PE
Fu
Mingui
M
D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D005810:Multigene Family / Q000235:genetics / Q000276:immunology*; D009569:Nitric Oxide / Q000276:immunology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000276:immunology; D010587:Phagocytosis / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology*; D016335:Zinc Fingers / Q000235:genetics / Q000276:immunology*
D016207:Cytokines; D008070:Lipopolysaccharides; D014157:Transcription Factors; D009569:Nitric Oxide; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse