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 Blood, 15 October 2008, Vol. 112, No. 8, pp. 3274-3282.
Prepublished online as a Blood First Edition Paper on August 5, 2008; DOI 10.1182/blood-2007-11-123604.

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IMMUNOBIOLOGY

IFN-{gamma}–mediated inhibition of MAPK phosphatase expression results in prolonged MAPK activity in response to M-CSF and inhibition of proliferation

Annabel F. Valledor1, Luís Arpa2, Ester Sánchez-Tilló2, Mònica Comalada2, Cristina Casals2, Jordi Xaus2, Carme Caelles3, Jorge Lloberas2, and Antonio Celada2

1 Nuclear Receptor Group, Department of Physiology, School of Biology, University of Barcelona, Barcelona; and 2 Macrophage Biology Group and 3 Cell Signaling Group, Institute for Research in Biomedicine (IRB) and University of Barcelona, Barcelona, Spain

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.


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