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 (Berl). 2012 Nov;90(11):1295-309. doi: 10.1007/s00109-012-0907-y. Epub 2012 May 19.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Arthritis, Rheumatoid / blood*
  • Cytokines / metabolism*
  • Female
  • Gene Expression Regulation*
  • Humans
  • Inflammation
  • Interferon Type I / metabolism*
  • Interferon-alpha / metabolism
  • Interferon-gamma / metabolism*
  • Lupus Erythematosus, Systemic / blood*
  • Male
  • Middle Aged
  • Monocytes / cytology
  • Monocytes / metabolism*
  • STAT1 Transcription Factor / metabolism
  • Tumor Necrosis Factor-alpha / metabolism*


  • Cytokines
  • Interferon Type I
  • Interferon-alpha
  • STAT1 Transcription Factor
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma