title: The multifaceted balance of TNF-α and type I/II interferon responses in SLE and RA: how monocytes manage the impact of cytokines.
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.
authors.affiliation: Deutsches Rheuma-Forschungszentrum Berlin (DRFZ), Ein Leibniz-Institut, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Biljana
authors.initials: B
authors.lastname: Smiljanovic
authors.forename: Joachim R
authors.initials: JR
authors.lastname: Grün
authors.forename: Robert
authors.initials: R
authors.lastname: Biesen
authors.forename: Ursula
authors.initials: U
authors.lastname: Schulte-Wrede
authors.forename: Ria
authors.initials: R
authors.lastname: Baumgrass
authors.forename: Bruno
authors.initials: B
authors.lastname: Stuhlmüller
authors.forename: Wlodzimierz
authors.initials: W
authors.lastname: Maslinski
authors.forename: Falk
authors.initials: F
authors.lastname: Hiepe
authors.forename: Gerd-R
authors.initials: GR
authors.lastname: Burmester
authors.forename: Andreas
authors.initials: A
authors.lastname: Radbruch
authors.forename: Thomas
authors.initials: T
authors.lastname: Häupl
authors.forename: Andreas
authors.initials: A
authors.lastname: Grützkau
mesh_terms: D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000097:blood*; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation; D007370:Interferon Type I / Q000378:metabolism*; D016898:Interferon-alpha / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism*; D008180:Lupus Erythematosus, Systemic / Q000097:blood*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000166:cytology / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D016207:Cytokines; D007370:Interferon Type I; D016898:Interferon-alpha; D050794:STAT1 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma