An essential role for STAT6-STAT1 protein signaling in promoting macrophage cell-cell fusion

J Biol Chem. 2012 Sep 21;287(39):32479-84. doi: 10.1074/jbc.M112.358226. Epub 2012 Aug 3.

Abstract

Macrophage lineage cells such as osteoclasts and foreign body giant cells (FBGCs) form multinuclear cells by cell-cell fusion of mononuclear cells. Recently, we reported that two seven-transmembrane molecules, osteoclast stimulatory transmembrane protein (OC-STAMP) and dendritic cell-specific transmembrane protein (DC-STAMP), were essential for osteoclast and FBGC cell-cell fusion in vivo and in vitro. However, signaling required to regulate FBGC fusion remained largely unknown. Here, we show that signal transducer and activator of transcription 1 (STAT1) deficiency in macrophages enhanced cell-cell fusion and elevated DC-STAMP expression in FBGCs. By contrast, lack of STAT6 increased STAT1 activation, significantly inhibiting cell-cell fusion and decreasing OC-STAMP and DC-STAMP expression in IL-4-induced FBGCs. Furthermore, either STAT1 loss or co-expression of OC-STAMP/DC-STAMP was sufficient to induce cell-cell fusion of FBGCs without IL-4. We conclude that the STAT6-STAT1 axis regulates OC-STAMP and DC-STAMP expression and governs fusogenic mechanisms in FBGCs.

MeSH terms

  • Animals
  • Cell Fusion
  • Gene Expression Regulation / physiology
  • Giant Cells, Foreign-Body / cytology
  • Giant Cells, Foreign-Body / metabolism*
  • Interleukin-4 / genetics
  • Interleukin-4 / metabolism
  • Membrane Proteins / biosynthesis*
  • Membrane Proteins / genetics
  • Mice
  • Mice, Knockout
  • Nerve Tissue Proteins / biosynthesis*
  • Nerve Tissue Proteins / genetics
  • STAT1 Transcription Factor / genetics
  • STAT1 Transcription Factor / metabolism*
  • STAT6 Transcription Factor / genetics
  • STAT6 Transcription Factor / metabolism*
  • Signal Transduction / physiology*

Substances

  • DC-STAMP protein, mouse
  • Membrane Proteins
  • Nerve Tissue Proteins
  • OC-STAMP protein, mouse
  • STAT1 Transcription Factor
  • STAT6 Transcription Factor
  • Stat1 protein, mouse
  • Stat6 protein, mouse
  • Interleukin-4