Selective roles of MAPKs during the macrophage response to IFN-gamma.
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.
Valledor
Annabel F
AF
Nuclear Receptors Group, Department of Physiology, School of Biology, Institute for Research in Biomedicine (IRB), Barcelona, Spain.
Sánchez-Tilló
Ester
E
Arpa
Luis
L
Park
Jin Mo
JM
Caelles
Carme
C
Lloberas
Jorge
J
Celada
Antonio
A
D000818:Animals; D002478:Cells, Cultured; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007371:Interferon-gamma / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology*; D051379:Mice; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010768:Phosphoserine / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D020871:RNA Stability / Q000187:drug effects; D050794:STAT1 Transcription Factor / Q000378:metabolism
D047428:Protein Kinase Inhibitors; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D010768:Phosphoserine; D007371:Interferon-gamma; D020928:Mitogen-Activated Protein Kinases