Macrophage differentiation of myeloid progenitor cells in response to M-CSF is regulated by the dual-specificity phosphatase DUSP5.
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.
Universite de Lyon, Universite Lyon 1, Centre de Genetique Moleculaire et Cellulaire, CNRS UMR5534, Villeurbanne, France.
Marie-France
MF
Grasset
Stéphanie
S
Gobert-Gosse
Guy
G
Mouchiroud
Roland P
RP
Bourette
D051722:ADAM Proteins / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics; D002070:Butadienes / Q000494:pharmacology; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects; D054637:Dual-Specificity Phosphatases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology*; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D039902:Multipotent Stem Cells / Q000187:drug effects*; D038042:Myelopoiesis / Q000187:drug effects* / Q000235:genetics; D009570:Nitriles / Q000494:pharmacology; D053495:Osteopontin / Q000096:biosynthesis / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000187:drug effects / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000187:drug effects / Q000502:physiology
D015703:Antigens, CD; D002070:Butadienes; D008565:Membrane Proteins; D009570:Nitriles; D011993:Recombinant Fusion Proteins; C506896:Spp1 protein, mouse; C113580:U 0126; D053495:Osteopontin; D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C442320:DUSP5 protein, human; D054637:Dual-Specificity Phosphatases; C546197:Dusp5 protein, mouse; D051722:ADAM Proteins; C489402:Adam8 protein, mouse