Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Article
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Marrack P, Kappler J, Kotzin BL (2001) Autoimmune disease: why and where it occurs. Nat Med 7:899–905. doi:10.1038/90935

    Article  PubMed  CAS  Google Scholar 

  2. Ronnblom L, Elkon KB (2010) Cytokines as therapeutic targets in SLE. Nat Rev Rheumatol 6:339–347. doi:10.1038/nrrheum.2010.64

    Article  PubMed  Google Scholar 

  3. McInnes IB, Schett G (2007) Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol 7:429–442

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  5. Burmester GR, Haupl T (2004) Strategies using functional genomics in rheumatic diseases. Autoimmun Rev 3:541–549

    Article  PubMed  CAS  Google Scholar 

  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 6:388–397

    Article  CAS  Google Scholar 

  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 13:59–68

    Article  PubMed  CAS  Google Scholar 

  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 100:2610–2615

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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 11:21–29

    Article  PubMed  CAS  Google Scholar 

  12. Baechler EC, Gregersen PK, Behrens TW (2004) The emerging role of interferon in human systemic lupus erythematosus. Curr Opin Immunol 16:801–807

    Article  PubMed  CAS  Google Scholar 

  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

    Article  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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 31–40

    Chapter  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  19. Gordon S, Taylor PR (2005) Monocyte and macrophage heterogeneity. Nat Rev Immunol 5:953–964

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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 95:15623–15628

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  28. van Boxel-Dezaire AH, Stark GR (2007) Cell type-specific signaling in response to interferon-gamma. Curr Top Microbiol Immunol 316:119–154

    Article  PubMed  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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:e491

    Article  PubMed  Google Scholar 

  32. Ramana CV, Gil MP, Schreiber RD, Stark GR (2002) Stat1-dependent and -independent pathways in IFN-gamma-dependent signaling. Trends Immunol 23:96–101

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  36. Feldmann M (2002) Development of anti-TNF therapy for rheumatoid arthritis. Nat Rev Immunol 2:364–371. doi:10.1038/nri802

    Article  PubMed  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. Deutsches Rheuma-Forschungszentrum Berlin (DRFZ), Ein Leibniz-Institut, Charitéplatz 1, 10117, Berlin, Germany

    Biljana Smiljanovic, Joachim R. Grün, Ursula Schulte-Wrede, Ria Baumgrass, Andreas Radbruch & Andreas Grützkau

  2. Department of Rheumatology and Clinical Immunology, Charité Universitätsmedizin Berlin, Humboldt University of Berlin, Berlin, Germany

    Robert Biesen, Bruno Stuhlmüller, Falk Hiepe, Gerd-R Burmester & Thomas Häupl

  3. Department of Pathophysiology and Immunology, Institute of Rheumatology, Warsaw, Poland

    Wlodzimierz Maslinski

Authors
  1. Biljana Smiljanovic
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joachim R. Grün
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Robert Biesen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ursula Schulte-Wrede
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ria Baumgrass
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Bruno Stuhlmüller
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wlodzimierz Maslinski
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Falk Hiepe
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Gerd-R Burmester
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Andreas Radbruch
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Thomas Häupl
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Andreas Grützkau
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Andreas Grützkau.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(XLS 1,551 kb)

ESM 2

(XLS 5,621 kb)

ESM 3

(XLS 2,841 kb)

ESM 4

(XLS 31 kb)

ESM 5

(XLS 62 kb)

ESM 6

(PDF 1.35  MB)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Smiljanovic, B., Grün, J.R., Biesen, R. et al. The multifaceted balance of TNF-α and type I/II interferon responses in SLE and RA: how monocytes manage the impact of cytokines. J Mol Med 90, 1295–1309 (2012). https://doi.org/10.1007/s00109-012-0907-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-012-0907-y

Keywords

Search

Navigation