The multifaceted balance of TNF-α and type I/II interferon responses in SLE and RA: how monocytes manage the impact of cytokines
B Smiljanovic, JR Grün, R Biesen… - Journal of molecular …, 2012 - Springer
B Smiljanovic, JR Grün, R Biesen, U Schulte-Wrede, R Baumgrass, B Stuhlmüller…
Journal of molecular medicine, 2012•SpringerMany 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 …
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 …
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.
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