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Journal of Molecular Medicine

, Volume 90, Issue 11, pp 1295–1309 | Cite as

The multifaceted balance of TNF-α and type I/II interferon responses in SLE and RA: how monocytes manage the impact of cytokines

  • Biljana Smiljanovic
  • Joachim R. Grün
  • Robert Biesen
  • Ursula Schulte-Wrede
  • Ria Baumgrass
  • Bruno Stuhlmüller
  • Wlodzimierz Maslinski
  • Falk Hiepe
  • Gerd-R Burmester
  • Andreas Radbruch
  • Thomas Häupl
  • Andreas Grützkau
Original Article

Abstract

Many cytokines are involved in the pathogenesis of autoimmune diseases and are recognized as relevant therapeutic targets to attenuate inflammation, such as tumor necrosis factor (TNF)-α in rheumatoid arthritis (RA) and interferon (IFN)-α/γ in systemic lupus erythematosus (SLE). To relate the transcriptional imprinting of cytokines in a cell type- and disease-specific manner, we generated gene expression profiles from peripheral monocytes of SLE and RA patients and compared them to in vitro-generated signatures induced by TNF-α, IFN-α2a, and IFN-γ. Monocytes from SLE and RA patients revealed disease-specific gene expression profiles. In vitro-generated signatures induced by IFN-α2a and IFN-γ showed similar profiles that only partially overlapped with those induced by TNF-α. Comparisons between disease-specific and in vitro-generated signatures identified cytokine-regulated genes in SLE and RA with qualitative and quantitative differences. The IFN responses in SLE and RA were found to be regulated in a STAT1-dependent and STAT1-independent manner, respectively. Similarly, genes recognized as TNF-α regulated were clearly distinguishable between RA and SLE patients. While the activity of SLE monocytes was mainly driven by IFN, the activity from RA monocytes showed a dominance of TNF-α that was characterized by STAT1 down-regulation. The responses to specific cytokines were revealed to be disease-dependent and reflected the interplay of cytokines within various inflammatory milieus. This study has demonstrated that monocytes from RA and SLE patients exhibit disease-specific gene expression profiles, which can be molecularly dissected when compared with in vitro-generated cytokine signatures. The results suggest that an assessment of cytokine-response status in monocytes may be helpful for improvement of diagnosis and selection of the best cytokine target for therapeutic intervention.

Keywords

Monocytes RA SLE Transcriptome IFN-α/γ TNF-α 

Notes

Acknowledgments

We are grateful to Heidi Schliemann for generating the gene expression data and to Dr. Hans-Joachim Mollenkopf for valuable discussion.

Funding source

The work was supported by the German Ministry of Education and Research (BMBF) within the National Genome Research Network NGFN (01GS0413) and ArthroMark (01EC1009A), by the European Union’s Sixth Framework Programme (project AutoCure; LSHB-CT-2006-018861), and by the IMI JU funded project BeTheCure, contract no 115142-2.

Authorship

Conceived and designed the research: AG, AR, BS, TH, WM, RBa, GRB. Performed research: BS, AG, RB. Analyzed data: BS, AG, RBa, JG, USW, TH, FH, BSt. Wrote the paper: BS, AG, TH.

Conflict of interest

The authors declare no conflict of interest.

Supplementary material

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Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Biljana Smiljanovic
    • 1
  • Joachim R. Grün
    • 1
  • Robert Biesen
    • 2
  • Ursula Schulte-Wrede
    • 1
  • Ria Baumgrass
    • 1
  • Bruno Stuhlmüller
    • 2
  • Wlodzimierz Maslinski
    • 3
  • Falk Hiepe
    • 2
  • Gerd-R Burmester
    • 2
  • Andreas Radbruch
    • 1
  • Thomas Häupl
    • 2
  • Andreas Grützkau
    • 1
  1. 1.Deutsches Rheuma-Forschungszentrum Berlin (DRFZ)Ein Leibniz-InstitutBerlinGermany
  2. 2.Department of Rheumatology and Clinical ImmunologyCharité Universitätsmedizin Berlin, Humboldt University of BerlinBerlinGermany
  3. 3.Department of Pathophysiology and ImmunologyInstitute of RheumatologyWarsawPoland

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