Regulatory Feedback Loop Between NF-kappaB and MCP-1-induced Protein 1 RNase

FEBS J. 2009 Oct;276(20):5892-905. doi: 10.1111/j.1742-4658.2009.07273.x. Epub 2009 Sep 11.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Binding Sites / genetics
  • Blotting, Western
  • Cell Line, Tumor
  • Chromatin Immunoprecipitation
  • Electrophoretic Mobility Shift Assay
  • Humans
  • I-kappa B Proteins / genetics
  • I-kappa B Proteins / physiology
  • Interleukin-1beta / pharmacology
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Polymerase Chain Reaction
  • Ribonucleases
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription Initiation Site
  • Transcription, Genetic / genetics

Substances

  • I-kappa B Proteins
  • Interleukin-1beta
  • NF-kappa B
  • Transcription Factors
  • Ribonucleases
  • ZC3H12A protein, human