title: 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.
abstract: 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 α (TNFα) was shown to induce a delayed IFN response in macrophages. We undertook this study to test whether TNFα, classically thought to activate inflammatory NF-κB 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 TNFα. Expression of IFN-inducible target genes was measured by quantitative reverse transcription-polymerase 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 TNFα were blocked, whereas TNFα 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 TNFα-, IFNα-, and IFNβ-stimulated control macrophages. Type I IFNs suppressed expression of IL8 and MMP9 in RA synovial macrophages and in TNFα-stimulated control macrophages.
  
  
  CONCLUSIONS
  Our findings identify a new function of TNFα in RA synovitis by implicating TNFα 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 TNFα and opposing homeostatic factors expressed in the synovial microenvironment.
authors.affiliation: Hospital for Special Surgery, New York, New York 10021, USA.
authors.forename: Rachael A
authors.initials: RA
authors.lastname: Gordon
authors.forename: Galina
authors.initials: G
authors.lastname: Grigoriev
authors.forename: Angela
authors.initials: A
authors.lastname: Lee
authors.forename: George D
authors.initials: GD
authors.lastname: Kalliolias
authors.forename: Lionel B
authors.initials: LB
authors.lastname: Ivashkiv
mesh_terms: D000328:Adult; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007370:Interferon Type I / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D025241:Spondylarthritis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D013582:Synovial Fluid / Q000166:cytology / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D007370:Interferon Type I; D016209:Interleukin-8; D050794:STAT1 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D020780:Matrix Metalloproteinase 9