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02.24 The ap-1 transcription factor c-jun promotes arthritis by regulating cyclooxygenase-2 expression in macrophages
  1. Nicole Hannemann1,
  2. Jutta Jordan2,
  3. Sushmita Paul3,
  4. Stephen Reid4,
  5. Hanns-Wolf Baenkler1,
  6. Sophia Sonnewald4,
  7. Tobias Bäuerle2,
  8. Julio Vera3,
  9. Georg Schett1,
  10. Aline Bozec1
  1. 1Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Department of Internal Medicine 3 – Rheumatology and Immunology, Universitätsklinikum Erlangen, Erlangen, Germany
  2. 2Institute of Radiology, Preclinical Imaging Platform Erlangen (PIPE) Universitätsklinikum Erlangen, Erlangen, Germany
  3. 3Department of Dermatology, Laboratory of Systems Tumour Immunology Universitätsklinikum Erlangen, Erlangen, Germany
  4. 4Division of Biochemistry, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Germany


Background Pro-inflammatory macrophage activation is associated with the inflammatory state of rheumatoid arthritis (RA). Their polarisation and activation are controlled by transcription factors, such as NF-κB and the AP-1 transcription factor members JunB or JunD. However, the role of the third JUN/AP-1 member, c-Jun, is still ill defined during macrophage activation in RA.

Material and methods To examine the role of c-Jun during macrophage activation, c-Jun deleted peritoneal macrophages were used for microarray and quantitative real-time PCR analysis. In addition, genes found differentially expressed were analysed by chromatin immunoprecipitation (ChIP) analysis to determine directs targets of c-Jun. To address the physiological role of c-Jun in macrophages, the serum induced arthritis (K/BxN) model was applied to c-JunΔLysM mice.

Results C-Jun mRNA and protein levels are increased in macrophages following pro- or anti-inflammatory stimulations. Gene Ontology (GO) and KEGG pathway enrichment cluster analyses of microarray data using wild-type and c-Jun deleted macrophages highlight the central function of c-Jun, in particular for immune response, interleukin production and hypoxia pathways. Mice deficient for c-Jun in macrophages showed an amelioration of inflammation and bone destruction in the K/BxN arthritis model. In vivo and in vitro gene profiling, together with ChIP analysis in macrophages unravelled direct activation of the pro-inflammatory factor cyclooxygenase-2 (Cox2) and indirect inhibition of the anti-inflammatory factor arginase-1 (Arg1) by c-Jun.

Conclusion Thus, c-Jun regulates the activation state of macrophages and promotes arthritis via differentially regulating Cox2 and Arg1 levels.

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