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