title: IFN-{gamma}-mediated inhibition of MAPK phosphatase expression results in prolonged MAPK activity in response to M-CSF and inhibition of proliferation.
abstract: Macrophages have the capacity to proliferate in response to specific growth factors, such as macrophage-colony stimulating factor (M-CSF). In the presence of several cytokines and activating factors, macrophages undergo growth arrest, become activated, and participate in the development of an immune response. We have previously observed that activation of extracellularly regulated kinase 1/2 (ERK-1/2) is required for macrophage proliferation in response to growth factors. A short and early pattern of ERK activity correlated with the proliferative response. In contrast, slightly prolonged patterns of activity of these kinases were induced by signals that lead to macrophage activation and growth arrest. IFN-gamma is the main endogenous Th1-type macrophage activator. Here we report that stimulation with IFN-gamma prolongs the pattern of ERK activity induced by M-CSF in macrophages. These effects correlate with IFN-gamma-mediated inhibition of the expression of several members of the MAPK phosphatase family, namely MKP-1, -2, and -4. Moreover, inhibition of MKP-1 expression using siRNA technology or synthetic inhibitors also led to elongated ERK activity and significant blockage of M-CSF-dependent proliferation. These data suggest that subtle changes in the time course of activity of members of the MAPK family contribute to the antiproliferative effects of IFN-gamma in macrophages.
authors.affiliation: Nuclear Receptor Group, Department of Physiology, School of Biology, University of Barcelona, Barcelona, Spain.
authors.forename: Annabel F
authors.initials: AF
authors.lastname: Valledor
authors.forename: Luís
authors.initials: L
authors.lastname: Arpa
authors.forename: Ester
authors.initials: E
authors.lastname: Sánchez-Tilló
authors.forename: Mònica
authors.initials: M
authors.lastname: Comalada
authors.forename: Cristina
authors.initials: C
authors.lastname: Casals
authors.forename: Jordi
authors.initials: J
authors.lastname: Xaus
authors.forename: Carme
authors.initials: C
authors.lastname: Caelles
authors.forename: Jorge
authors.initials: J
authors.lastname: Lloberas
authors.forename: Antonio
authors.initials: A
authors.lastname: Celada
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D018797:Cell Cycle Proteins; D049109:Cell Proliferation; D054638:Dual Specificity Phosphatase 1 / Q000096:biosynthesis*; D015971:Gene Expression Regulation, Enzymologic; D007371:Interferon-gamma / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008262:Macrophage Activation; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D008264:Macrophages / Q000201:enzymology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010641:Phenotype; D015398:Signal Transduction
chemical_list: D018797:Cell Cycle Proteins; D016173:Macrophage Colony-Stimulating Factor; D007371:Interferon-gamma; D054638:Dual Specificity Phosphatase 1