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J Immunol. 2017 May 1;198(9):3605-3614. doi: 10.4049/jimmunol.1601330. Epub 2017 Mar 15.

The AP-1 Transcription Factor c-Jun Promotes Arthritis by Regulating Cyclooxygenase-2 and Arginase-1 Expression in Macrophages.

Author information

1
Department of Internal Medicine 3-Rheumatology and Immunology, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg, 91054 Erlangen, Germany.
2
Preclinical Imaging Platform Erlangen, Institute of Radiology, University Hospital Erlangen, 91054 Erlangen, Germany.
3
Laboratory of Systems Tumor Immunology, Department of Dermatology, University Hospital Erlangen, 91054 Erlangen, Germany; and.
4
Division of Biochemistry, Friedrich Alexander University Erlangen-Nuremberg, 91054 Erlangen, Germany.
5
Department of Internal Medicine 3-Rheumatology and Immunology, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg, 91054 Erlangen, Germany; aline.bozec@uk-erlangen.de.

Abstract

Activation of proinflammatory macrophages is associated with the inflammatory state of rheumatoid arthritis. Their polarization and activation are controlled by transcription factors such as NF-κB and the AP-1 transcription factor member c-Fos. Surprisingly, little is known about the role of the AP-1 transcription factor c-Jun in macrophage activation. In this study, we show that mRNA and protein levels of c-Jun are increased in macrophages following pro- or anti-inflammatory stimulations. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment cluster analyses of microarray data using wild-type and c-Jun-deleted macrophages highlight the central function of c-Jun in macrophages, in particular for immune responses, IL production, and hypoxia pathways. Mice deficient for c-Jun in macrophages show an amelioration of inflammation and bone destruction in the serum-induced arthritis model. In vivo and in vitro gene profiling, together with chromatin immunoprecipitation analysis of macrophages, revealed direct activation of the proinflammatory factor cyclooxygenase-2 and indirect inhibition of the anti-inflammatory factor arginase-1 by c-Jun. Thus, c-Jun regulates the activation state of macrophages and promotes arthritis via differentially regulating cyclooxygenase-2 and arginase-1 levels.

PMID:
28298526
DOI:
10.4049/jimmunol.1601330
[Indexed for MEDLINE]
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