The interferon signature and STAT1 expression in rheumatoid arthritis synovial fluid macrophages are induced by tumor necrosis factor α and counter-regulated by the synovial fluid microenvironment

Objective Type I interferons (IFNs) have emerged as potential activators of the IFN signature and elevated STAT-1 expression in rheumatoid arthritis (RA) synovium, but mechanisms that induce synovial IFN expression are unknown. Recently, tumor necrosis factor a (TNF alpha) was shown to induce a delayed IFN response in macrophages. We undertook this study to test whether TNF alpha, classically thought to activate inflammatory NF-kappa B target genes in RA, also contributes to the IFN signature in RA synovial macrophages. Methods Synovial fluid (SF) macrophages purified from 24 patients with RA and 18 patients with spondylarthritides (SpA) were lysed immediately after isolation or were cultured ex vivo in the absence or presence of blockade of endogenous type I IFN or TNF alpha. Expression of IFN-inducible target genes was measured by quantitative reverse transcriptionpolymerase chain reaction, and expression of their corresponding proteins was measured by enzyme-linked immunosorbent assay. Results Expression of an IFN signature and STAT1 in RA synovial macrophages was suppressed when type I IFNs or TNF alpha were blocked, whereas TNF alpha blockade did not affect expression of IFN response genes or STAT1 in SpA synovial macrophages. RA SF suppressed the IFN signature in RA synovial macrophages and in TNF alpha-, IFN alpha-, and IFN beta-stimulated control macrophages. Type I IFNs suppressed expression of IL8 and MMP9 in RA synovial macrophages and in TNF alpha-stimulated control macrophages. Conclusion Our findings identify a new function of TNFa in RA synovitis by implicating TNFa as a major inducer of the RA synovial IFN response. The results suggest that the expression of IFN response genes in RA synovium is regulated by interplay between TNF alpha and opposing homeostatic factors expressed in the synovial microenvironment.