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Type I interferons might form the link between Toll-like receptor (TLR) 3/7 and TLR4 mediated synovial inflammation in rheumatoid arthritis (RA).
  1. M F. Roelofs (m.roelofs{at}reuma.umcn.nl)
  1. Radboud University Nijmegen Medical Center, Netherlands
    1. M H Wenink (m.wenink{at}reuma.umcn.nl)
    1. Radboud University Nijmegen Medical Center, Netherlands
      1. F Brentano (fabia.brentano{at}usz.ch)
      1. University Hospital, Zurich, Switzerland
        1. S Abdollahi-Roodsaz (s.abdollahi-roodsaz{at}reuma.umcn.nl)
        1. Radboud University Nijmegen Medical Center, Netherlands
          1. B Oppers-Walgreen (b.oppers-walgreen{at}reuma.umcn.nl)
          1. Radboud University Nijmegen Medical Center, Netherlands
            1. P Barrera (p.barrera{at}reuma.umcn.nl)
            1. Radboud University Nijmegen Medical Center, Netherlands
              1. P LCM van Riel (p.vanriel{at}reuma.umcn.nl)
              1. Radboud University Nijmegen Medical Center, Netherlands
                1. L AB Joosten
                1. Radboud University Nijmegen Medical Center, Netherlands
                  1. D Kyburz (diego.kyburz{at}usz.ch)
                  1. University Hospital, Zurich, Switzerland
                    1. W B van den Berg (w.vandenberg{at}reuma.umcn.nl)
                    1. Radboud University Nijmegen Medical Center, Netherlands
                      1. T RDJ Radstake (t.radstake{at}reuma.umcn.nl)
                      1. Radboud University Nijmegen Medical Center, Netherlands

                        Abstract

                        Rationale: Rheumatoid arthritis (RA) hasbeen associated with increased risk for infections but the underlying pathways have not been identified yet. Toll like receptors (TLR) play probably a role in synovial inflammation and may also contribute to our understanding on the role of infections in RA.

                        Objective: To investigate if the synovial expression of Toll-like receptor (TLR) 3 and TLR7 in RA correlates with that of inflammatory cytokines. To assess whether this has functional consequences for the local cytokine production and to study potential links between TLR3/7 axis and TLR4 in RA synovium.

                        Methods: Immunohistochemistry was used to study the expression of TLR3, TLR7, IFNα, TNFα, IL-1β, IL-12, IL-17 and IL-18 in RA synovium from 34 RA patients obtained via arthroscopy. Monocytes, monocyte-derived dendritic cells (MoDC) and RA synovial fibroblasts were stimulated via TLR3 (Poly-IC) and TLR7 (loxorubin) after which IL-1β, IL-6 and TNFα was measured by Luminex bead array technology. Upon pre-incubation with IFNα, IL-1β and IL-18 TLR3 and TLR7 mRNA expression was assessed using real-time PCR. Cytokine production after pre-incubation with IFNα and subsequent TLR stimulation was measured.

                        Results: Synovial TLR3/7 expression was co-expressed with IFNα, IL-1β and IL-18, but not with TNFα, IL-12 and IL-17. Stimulation of TLR3/TLR7 on monocytes, MoDC or synovial fibroblasts led to secretion of type I IFN whereas no biologically active IL-1β or IL-18 could be detected. Type I IFNα increased TLR3/7 mRNA expression whereas IL-1β and IL-18 did not. Strikingly, in spite of the fact that the mRNA level of TLR4 remained unchanged, IFNα enhanced the response to TLR4 agonists, a phenomenon that was clearly more marked in RA patients.

                        Conclusion: Type I interferons are highly co-expressed with TLR3/TLR7 in RA synovium. Furthermore, they enhance not only TLR3/TLR7 mediated cytokine production but also TLR4 mediated responses.

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