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.

IFNα and its response proteins, IP-10 and SIGLEC-1, are biomarkers of disease activity in systemic lupus erythematosus

“…Whereas the specificity of ELISAs that detect IFNα has been questioned,13 indirect assessment of IFN activity has been reported to be much more sensitive 14–16. It should be noted that non-specific induction of IFITs and proteins by other IFNs17 and cytokines18 may contribute to this observation.…”

Upcoming value of gene expression analysis in rheumatology

“…Это может свидетельствовать о том, что нейтрализация TNFa у данных больных способствует повышению экспрессии генов, которые прежде были подавлены TNFa [30]. С другой стороны, повышение биоактивности IFN в процессе терапии РА можно расценивать либо как неблагоприятный симптом, либо как свидетельство неудавшейся попытки подавить воспаление [25].…”

Flavonoids from Litsea coreana Decreases TNF-α Secretion from Peritoneal Macrophages in Adjuvant-Induced Arthritis Rats via UPR Pathway

“…Activated peritoneal macrophages play an important role in RA through the release of inflammatory mediators, including TNF-. Although emerging evidence suggest that TNF-plays a central role in the etiopathogenesis of chronic inflammatory and destructive process of RA (Smiljanovic et al, 2012), the etiology and pathogenesis of RA are still not clear up to now. Previous studies have reported that RA has close relation to endoplasmic reticulum (ER) stress (Yamasaki et al, 2007;Shin et al, 2010).…”