Selective Roles of Mapks during the Macrophage Response to Ifn-

Valledor, A.F.; Sanchez-Tillo, E.; Arpa, L.; Park, J.M.; Caelles, C.; Lloberas, J.; Celada, A.

The Journal of Immunology 180(7): 4523-4529

2008


DOI: 10.4049/jimmunol.180.7.4523
Accession: 068490987

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Abstract
Macrophages perform essential functions in the infection and resolution of inflammation. IFN-gamma is the main endogenous macrophage Th1 type activator. The classical IFN-gamma signaling pathway involves activation of Stat-1. However, IFN-gamma has also the capability to activate members of the MAPK family. In primary bone marrow-derived macrophages, we have observed strong activation of p38 at early time points of IFN-gamma stimulation, whereas weak activation of ERK-1/2 and JNK-1 was detected at a more delayed stage. In parallel, IFN-gamma exerted repressive effects on the expression of a number of MAPK phosphatases. By using selective inhibitors and knockout models, we have explored the contributions of MAPK activation to the macrophage response to IFN-gamma. Our findings indicate that these kinases regulate IFN-gamma-mediated gene expression in a rather selective way: p38 participates mainly in the regulation of the expression of genes required for the innate immune response, including chemokines such as CCL5, CXCL9, and CXCL10; cytokines such as TNF-alpha; and inducible NO synthase, whereas JNK-1 acts on genes involved in Ag presentation, including CIITA and genes encoding MHC class II molecules. Modest effects were observed for ERK-1/2 in these studies. Interestingly, some of the MAPK-dependent changes in gene expression observed in these studies are based on posttranscriptional regulation of mRNA stability.