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Selective Roles of MAPKs during the Macrophage Response to IFN-¹

Annabel F. Valledor^2,*, Ester Sánchez-Tilló^2,, Luis Arpa, Jin Mo Park, Carme Caelles, Jorge Lloberas and Antonio Celada^3,

^* Nuclear Receptors Group, Department of Physiology, School of Biology, Macrophage Biology Group, and Cell Signaling Group, Institute for Research in Biomedicine (IRB), and University of Barcelona, Barcelona, Spain; and Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129

Macrophages perform essential functions in the infection and resolution of inflammation. IFN- is the main endogenous macrophage Th1 type activator. The classical IFN- signaling pathway involves activation of Stat-1. However, IFN- 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- stimulation, whereas weak activation of ERK-1/2 and JNK-1 was detected at a more delayed stage. In parallel, IFN- 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-. Our findings indicate that these kinases regulate IFN--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-; 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the Comisión Interministerial de Ciencia y Tecnología (BFU2004-05725/BMC to A.C.) and the European Commission (International Reintegration Grant IRG-31137 to A.F.V.). A.F.V. was a Ramon y Cajal investigator. L.A. was supported by a predoctoral fellowship (Formació Personal Investigador, Generalitat de Catalunya).

² A.F.V. and E.S.T. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Antonio Celada, Macrophage Biology Group, Institute for Biomedical Research, Josep Samitier 1-5, 08028 Barcelona, Spain. E-mail address: acelada{at}ub.edu

⁴ Abbreviations used in this paper: DBR, 5,6-dichlorobenzimidazole 1-β-D-ribofuranoside; WT, wild type; TBS-T, TBS, 0.1% Tween 20; MKP, MAPK phosphatase; NOS2, inducible NO synthase.