Regulatory feedback loop between NF-kappaB and MCP-1-induced protein 1 RNase.
A novel gene ZC3H12A, encoding MCP-1-induced protein 1 (MCPIP), was recently identified in human peripheral blood monocytes treated with monocyte chemotactic protein 1 (MCP-1) and in human monocyte-derived macrophages stimulated with interleukin (IL)-1beta. These experiments revealed that the gene undergoes rapid and potent transcription induction upon stimulation with proinflammatory molecules, such as MCP-1, IL-1beta, tumour necrosis factor alpha and lipopolysaccharide. Here we show that the induction of ZC3H12A by IL-1beta is predominantly NF-kappaB-dependent because inhibition of this signalling pathway results in the impairment of ZC3H12A transcription activation. Our results indicate the presence of an IL-1beta-responding region within the second intron of the ZC3H12A gene, which contains four functional NF-kappaB-binding sites. Therefore, we propose that this transcription enhancer transduces a ZC3H12A transcription-inducing signal after IL-1beta stimulation. Recent reports suggest that MCPIP acts as a negative regulator of inflammatory processes because it is engaged in the degradation of transcripts coding for certain proinflammatory cytokines. Our observations provide evidence for a novel negative feedback loop in the activation of NF-kappaB and point to potential significance of MCPIP in the treatment of various pathological states, such as diabetes or cancer that involve disturbances in the functioning of the NF-kappaB system.
Skalniak
Lukasz
L
Department of Cell Biochemistry, Faculty of Biochemistry, Jagiellonian University, Krakow, Poland.
Mizgalska
Danuta
D
Zarebski
Adrian
A
Wyrzykowska
Paulina
P
Koj
Aleksander
A
Jura
Jolanta
J
D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000502:physiology; D053583:Interleukin-1beta / Q000494:pharmacology; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D012260:Ribonucleases; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D024363:Transcription Initiation Site; D014158:Transcription, Genetic / Q000235:genetics
D020672:I-kappa B Proteins; D053583:Interleukin-1beta; D016328:NF-kappa B; D014157:Transcription Factors; D012260:Ribonucleases; C510646:ZC3H12A protein, human