Macrophage differentiation of myeloid progenitor cells in response to M-CSF is regulated by the dual-specificity phosphatase DUSP5

J Leukoc Biol. 2010 Jan;87(1):127-35. doi: 10.1189/jlb.0309151. Epub 2009 Oct 2.

Abstract

M-CSF regulates the production, survival, and function of monocytes and macrophages. The MAPKs ERK1/2 are key elements for signal integration downstream of the M-CSFR, and their sustained activation is essential for macrophage differentiation. In this study, we sought to isolate genes whose induction by M-CSF is dependent on persistent MAPK activation, thereby being possibly involved in the commitment of myeloid progenitors to macrophage differentiation. Following SSH between cDNA libraries from FD-Fms cells stimulated by M-CSF for 8 h in the presence or the absence of the MEK inhibitor U0126, we isolated DUSP5. DUSP5 expression is induced by M-CSF in various myeloid cells and acts as a specific negative-feedback regulator of ERK1/2. In FD-Fms cells that proliferate and differentiate toward macrophages in response to M-CSF, overexpression of DUSP5 increased M-CSF-dependent proliferation and strongly decreased differentiation. Similarly, overexpression of DUSP5 in the multipotent EGER-Fms cells not only significantly increased M-CSF-induced proliferation and prevented macrophage differentiation but also favored granulocytic differentiation. Altogether, experiments demonstrated that DUSP5 is implicated in M-CSF signaling and suggested that it may influence myeloid cell fate.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins / biosynthesis
  • ADAM Proteins / genetics
  • Animals
  • Antigens, CD / biosynthesis
  • Antigens, CD / genetics
  • Butadienes / pharmacology
  • Cells, Cultured / cytology
  • Cells, Cultured / drug effects
  • Dual-Specificity Phosphatases / biosynthesis
  • Dual-Specificity Phosphatases / genetics
  • Dual-Specificity Phosphatases / physiology*
  • Gene Expression Regulation / drug effects
  • Humans
  • MAP Kinase Signaling System / drug effects
  • Macrophage Colony-Stimulating Factor / pharmacology*
  • Macrophages / cytology*
  • Membrane Proteins / biosynthesis
  • Membrane Proteins / genetics
  • Mice
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Multipotent Stem Cells / drug effects*
  • Myelopoiesis / drug effects*
  • Myelopoiesis / genetics
  • Nitriles / pharmacology
  • Osteopontin / biosynthesis
  • Osteopontin / genetics
  • Phosphorylation / drug effects
  • Protein Processing, Post-Translational / drug effects
  • Receptor, Macrophage Colony-Stimulating Factor / drug effects
  • Receptor, Macrophage Colony-Stimulating Factor / genetics
  • Recombinant Fusion Proteins / drug effects
  • Recombinant Fusion Proteins / physiology

Substances

  • Antigens, CD
  • Butadienes
  • Membrane Proteins
  • Nitriles
  • Recombinant Fusion Proteins
  • Spp1 protein, mouse
  • U 0126
  • Osteopontin
  • Macrophage Colony-Stimulating Factor
  • Receptor, Macrophage Colony-Stimulating Factor
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • DUSP5 protein, human
  • Dual-Specificity Phosphatases
  • Dusp5 protein, mouse
  • ADAM Proteins
  • Adam8 protein, mouse