The putative tumor suppressor Zc3h12d modulates toll-like receptor signaling in macrophages

Cell Signal. 2012 Feb;24(2):569-576. doi: 10.1016/j.cellsig.2011.10.011. Epub 2011 Oct 20.

Abstract

Toll-like receptors (TLR) are pivotal in macrophage activation. The molecular mechanisms controlling TLR signaling and macrophage activation are not completely understood. Zc3h12d is originally identified as a possible tumor suppressor gene. However, its function remains unknown. We here report that Zc3h12d negatively regulates TLR signaling and macrophage activation. Zc3h12d was enriched in spleen, lung and lymph node. In macrophages, the expression of Zc3h12d was remarkably induced by TLR ligands through JNK and NF-κB signal pathways. On the other hand, overexpression of Zc3h12d significantly inhibited TLR2 and TLR4 activation-induced JNK, ERK and NF-κB signaling as well as macrophage inflammation. Similar to Zc3h12a/MCPIP1, Zc3h12d also decreased the global cellular protein ubiquitination. These findings suggest that Zc3h12d is a novel negative feedback regulator of TLR signaling and macrophage activation and thus may play a role in host immunity and inflammatory diseases.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle Proteins
  • Endonucleases
  • Endoribonucleases
  • Extracellular Signal-Regulated MAP Kinases / genetics
  • Extracellular Signal-Regulated MAP Kinases / immunology
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Feedback, Physiological*
  • Gene Expression / immunology*
  • HEK293 Cells
  • Humans
  • Immunity, Innate*
  • Inflammation / genetics
  • Inflammation / immunology
  • Inflammation / metabolism*
  • MAP Kinase Kinase 4 / genetics
  • MAP Kinase Kinase 4 / immunology
  • MAP Kinase Kinase 4 / metabolism
  • Macrophage Activation / genetics
  • Macrophage Activation / immunology
  • Macrophages / cytology
  • Macrophages / immunology
  • Macrophages / metabolism*
  • Male
  • Mice
  • NF-kappa B / genetics
  • NF-kappa B / immunology
  • NF-kappa B / metabolism
  • Proteins / genetics
  • Proteins / immunology
  • Proteins / metabolism*
  • Signal Transduction / immunology*
  • Toll-Like Receptor 2 / genetics
  • Toll-Like Receptor 2 / immunology
  • Toll-Like Receptor 2 / metabolism
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / immunology
  • Toll-Like Receptor 4 / metabolism
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / immunology
  • Tumor Suppressor Proteins / metabolism*
  • Ubiquitination

Substances

  • Cell Cycle Proteins
  • NF-kappa B
  • Proteins
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Tumor Suppressor Proteins
  • Extracellular Signal-Regulated MAP Kinases
  • MAP Kinase Kinase 4
  • Endonucleases
  • Endoribonucleases
  • ZC3H12D protein, human
  • Zc3h12d protein, mouse