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


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.


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



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.


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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  1. 1.
    Marrack P, Kappler J, Kotzin BL (2001) Autoimmune disease: why and where it occurs. Nat Med 7:899–905. doi: 10.1038/90935 PubMedCrossRefGoogle Scholar
  2. 2.
    Ronnblom L, Elkon KB (2010) Cytokines as therapeutic targets in SLE. Nat Rev Rheumatol 6:339–347. doi: 10.1038/nrrheum.2010.64 PubMedCrossRefGoogle Scholar
  3. 3.
    McInnes IB, Schett G (2007) Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol 7:429–442PubMedCrossRefGoogle Scholar
  4. 4.
    Aringer M, Smolen JS (2008) The role of tumor necrosis factor-alpha in systemic lupus erythematosus. Arthritis Res Ther 10:202. doi: 10.1186/ar2341 PubMedCrossRefGoogle Scholar
  5. 5.
    Burmester GR, Haupl T (2004) Strategies using functional genomics in rheumatic diseases. Autoimmun Rev 3:541–549PubMedCrossRefGoogle Scholar
  6. 6.
    Batliwalla FM, Baechler EC, Xiao X, Li W, Balasubramanian S, Khalili H, Damle A, Ortmann WA, Perrone A, Kantor AB et al (2005) Peripheral blood gene expression profiling in rheumatoid arthritis. Genes Immunol 6:388–397CrossRefGoogle Scholar
  7. 7.
    Baechler EC, Bauer JW, Slattery CA, Ortmann WA, Espe KJ, Novitzke J, Ytterberg SR, Gregersen PK, Behrens TW, Reed AM (2007) An interferon signature in the peripheral blood of dermatomyositis patients is associated with disease activity. Mol Med 13:59–68PubMedCrossRefGoogle Scholar
  8. 8.
    Baechler EC, Batliwalla FM, Karypis G, Gaffney PM, Ortmann WA, Espe KJ, Shark KB, Grande WJ, Hughes KM, Kapur V et al (2003) Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci U S A 100:2610–2615PubMedCrossRefGoogle Scholar
  9. 9.
    van der Pouw Kraan TC, Wijbrandts CA, van Baarsen LG, Voskuyl AE, Rustenburg F, Baggen JM, Ibrahim SM, Fero M, Dijkmans BA, Tak PP et al (2007) Rheumatoid arthritis subtypes identified by genomic profiling of peripheral blood cells: assignment of a type I interferon signature in a subpopulation of patients. Ann Rheum Dis 66:1008–1014. doi: 10.1136/ard.2006.063412 PubMedCrossRefGoogle Scholar
  10. 10.
    Palucka AK, Blanck JP, Bennett L, Pascual V, Banchereau J (2005) Cross-regulation of TNF and IFN-alpha in autoimmune diseases. Proc Natl Acad Sci U S A 102:3372–3377. doi: 10.1073/pnas.0408506102 PubMedCrossRefGoogle Scholar
  11. 11.
    Batliwalla FM, Li W, Ritchlin CT, Xiao X, Brenner M, Laragione T, Shao T, Durham R, Kemshetti S, Schwarz E et al (2005) Microarray analyses of peripheral blood cells identifies unique gene expression signature in psoriatic arthritis. Mol Med 11:21–29PubMedCrossRefGoogle Scholar
  12. 12.
    Baechler EC, Gregersen PK, Behrens TW (2004) The emerging role of interferon in human systemic lupus erythematosus. Curr Opin Immunol 16:801–807PubMedCrossRefGoogle Scholar
  13. 13.
    Reynier F, Pachot A, Paye M, Xu Q, Turrel-Davin F, Petit F, Hot A, Auffray C, Bendelac N, Nicolino M et al (2010) Specific gene expression signature associated with development of autoimmune type-I diabetes using whole-blood microarray analysis. Genes Immunol 11:269–278. doi: 10.1038/gene.2009.112 CrossRefGoogle Scholar
  14. 14.
    Berry MP, Graham CM, McNab FW, Xu Z, Bloch SA, Oni T, Wilkinson KA, Banchereau R, Skinner J, Wilkinson RJ et al (2010) An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosis. Nature 466:973–977. doi: 10.1038/nature09247 PubMedCrossRefGoogle Scholar
  15. 15.
    van Baarsen LG, Wijbrandts CA, Rustenburg F, Cantaert T, van der Pouw Kraan TC, Baeten DL, Dijkmans BA, Tak PP, Verweij CL (2010) Regulation of IFN response gene activity during infliximab treatment in rheumatoid arthritis is associated with clinical response to treatment. Arthritis Res Ther 12:R11. doi: 10.1186/ar2912 PubMedCrossRefGoogle Scholar
  16. 16.
    Lyons PA, McKinney EF, Rayner TF, Hatton A, Woffendin HB, Koukoulaki M, Freeman TC, Jayne DR, Chaudhry AN, Smith KG (2010) Novel expression signatures identified by transcriptional analysis of separated leucocyte subsets in systemic lupus erythematosus and vasculitis. Ann Rheum Dis 69:1208–1213. doi: 10.1136/ard.2009.108043 PubMedCrossRefGoogle Scholar
  17. 17.
    Gruetzkau A, Radbruch A (2008) Separation of whole blood cells and its impact on gene expression. In: Bosio A, Gerstmeyer B (eds) Microarrays in Inflammation. Birkhaeuser Verlag, Basel, pp 31–40CrossRefGoogle Scholar
  18. 18.
    Grutzkau A, Grun J, Haupl T, Burmester GR, Radbruch A (2007) Gene expression in inflammatory rheumatic diseases. Dtsch Med Wochenschr 132:1888–1891. doi: 10.1055/s-2007-984982 PubMedCrossRefGoogle Scholar
  19. 19.
    Gordon S, Taylor PR (2005) Monocyte and macrophage heterogeneity. Nat Rev Immunol 5:953–964PubMedCrossRefGoogle Scholar
  20. 20.
    Kinne RW, Stuhlmuller B, Burmester GR (2007) Cells of the synovium in rheumatoid arthritis. Macrophages. Arthritis Res Ther 9:224. doi: 10.1186/ar2333 PubMedCrossRefGoogle Scholar
  21. 21.
    Jiang N, Reich CF 3rd, Pisetsky DS (2003) Role of macrophages in the generation of circulating blood nucleosomes from dead and dying cells. Blood 102:2243–2250. doi: 10.1182/blood-2002-10-3312 PubMedCrossRefGoogle Scholar
  22. 22.
    Biesen R, Demir C, Barkhudarova F, Grun JR, Steinbrich-Zollner M, Backhaus M, Haupl T, Rudwaleit M, Riemekasten G, Radbruch A et al (2008) Sialic acid-binding Ig-like lectin 1 expression in inflammatory and resident monocytes is a potential biomarker for monitoring disease activity and success of therapy in systemic lupus erythematosus. Arthritis Rheum 58:1136–1145. doi: 10.1002/art.23404 PubMedCrossRefGoogle Scholar
  23. 23.
    Stuhlmuller B, Haupl T, Hernandez MM, Grutzkau A, Kuban RJ, Tandon N, Voss JW, Salfeld J, Kinne RW, Burmester GR (2010) CD11c as a transcriptional biomarker to predict response to anti-TNF monotherapy with adalimumab in patients with rheumatoid arthritis. Clin Pharmacol Ther 87:311–321. doi: 10.1038/clpt.2009.244 PubMedCrossRefGoogle Scholar
  24. 24.
    Smiljanovic B, Grun JR, Steinbrich-Zollner M, Stuhlmuller B, Haupl T, Burmester GR, Radbruch A, Grutzkau A, Baumgrass R (2010) Defining TNF-alpha- and LPS-induced gene signatures in monocytes to unravel the complexity of peripheral blood transcriptomes in health and disease. J Mol Med 88:1065–1079. doi: 10.1007/s00109-010-0648-8 PubMedCrossRefGoogle Scholar
  25. 25.
    Kim SK, Lund J, Kiraly M, Duke K, Jiang M, Stuart JM, Eizinger A, Wylie BN, Davidson GS (2001) A gene expression map for Caenorhabditis elegans. Science 293:2087–2092. doi: 10.1126/science.1061603 PubMedCrossRefGoogle Scholar
  26. 26.
    Der SD, Zhou A, Williams BR, Silverman RH (1998) Identification of genes differentially regulated by interferon alpha, beta, or gamma using oligonucleotide arrays. Proc Natl Acad Sci U S A 95:15623–15628PubMedCrossRefGoogle Scholar
  27. 27.
    van Boxel-Dezaire AH, Rani MR, Stark GR (2006) Complex modulation of cell type-specific signaling in response to type I interferons. Immunity 25:361–372. doi: 10.1016/j.immuni.2006.08.014 PubMedCrossRefGoogle Scholar
  28. 28.
    van Boxel-Dezaire AH, Stark GR (2007) Cell type-specific signaling in response to interferon-gamma. Curr Top Microbiol Immunol 316:119–154PubMedCrossRefGoogle Scholar
  29. 29.
    Ramana CV, Gil MP, Han Y, Ransohoff RM, Schreiber RD, Stark GR (2001) Stat1-independent regulation of gene expression in response to IFN-gamma. Proc Natl Acad Sci U S A 98:6674–6679. doi: 10.1073/pnas.111164198 PubMedCrossRefGoogle Scholar
  30. 30.
    Gil MP, Bohn E, O'Guin AK, Ramana CV, Levine B, Stark GR, Virgin HW, Schreiber RD (2001) Biologic consequences of Stat1-independent IFN signaling. Proc Natl Acad Sci U S A 98:6680–6685. doi: 10.1073/pnas.111163898 PubMedCrossRefGoogle Scholar
  31. 31.
    Bauer JW, Baechler EC, Petri M, Batliwalla FM, Crawford D, Ortmann WA, Espe KJ, Li W, Patel DD, Gregersen PK et al (2006) Elevated serum levels of interferon-regulated chemokines are biomarkers for active human systemic lupus erythematosus. PLoS Med 3:e491PubMedCrossRefGoogle Scholar
  32. 32.
    Ramana CV, Gil MP, Schreiber RD, Stark GR (2002) Stat1-dependent and -independent pathways in IFN-gamma-dependent signaling. Trends Immunol 23:96–101PubMedCrossRefGoogle Scholar
  33. 33.
    Zhao LJ, Hua X, He SF, Ren H, Qi ZT (2011) Interferon alpha regulates MAPK and STAT1 pathways in human hepatoma cells. Virol J 8:157. doi: 10.1186/1743-422X-8-157 PubMedCrossRefGoogle Scholar
  34. 34.
    Taylor MW, Grosse WM, Schaley JE, Sanda C, Wu X, Chien SC, Smith F, Wu TG, Stephens M, Ferris MW et al (2004) Global effect of PEG-IFN-alpha and ribavirin on gene expression in PBMC in vitro. J Interferon Cytokine Res 24:107–118. doi: 10.1089/107999004322813354 PubMedCrossRefGoogle Scholar
  35. 35.
    Karonitsch T, Feierl E, Steiner CW, Dalwigk K, Korb A, Binder N, Rapp A, Steiner G, Scheinecker C, Smolen J et al (2009) Activation of the interferon-gamma signaling pathway in systemic lupus erythematosus peripheral blood mononuclear cells. Arthritis Rheum 60:1463–1471. doi: 10.1002/art.24449 PubMedCrossRefGoogle Scholar
  36. 36.
    Feldmann M (2002) Development of anti-TNF therapy for rheumatoid arthritis. Nat Rev Immunol 2:364–371. doi: 10.1038/nri802 PubMedCrossRefGoogle Scholar

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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