CLINICAL AND EPIDEMIOLOGICAL RESEARCH

Extended report

Type I interferons might form the link between Toll-like receptor (TLR) 3/7 and TLR4-mediated synovial inflammation in rheumatoid arthritis (RA)

M F Roelofs¹, M H Wenink¹, F Brentano², S Abdollahi-Roodsaz¹, B Oppers-Walgreen¹, P Barrera¹, P L C M van Riel¹, L A B Joosten¹, D Kyburz², W B van den Berg¹, T R D J Radstake¹

¹ Department of Rheumatology, Radboud University Nijmegen Medical Center, The Netherlands
² Center of Experimental Rheumatology, University Hospital, Zurich, Switzerland

^{Correspondence to} Dr T R D J Radstake, Department of Rheumatology, Radboud University Nijmegen Medical Center, Geert Grooteplein 8, 6500 HB Nijmegen, The Netherlands; t.radstake{at}reuma.umcn.nl

Background: Rheumatoid arthritis (RA) has been associated with an increased risk of infections, but the underlying pathways have not yet been identified. Toll-like receptors (TLR) probably play a role in synovial inflammation and may also contribute to the understanding of the role of infections in RA.

Objectives: To investigate if the synovial expression of TLR3 and TLR7 in RA correlates with that of inflammatory cytokines, and to assess whether this has functional consequences for local cytokine production and to study potential links between the TLR3/7 axis and TLR4 in RA synovium.

Methods: Immunohistochemistry was used to study the expression of TLR3, TLR7, interferon (IFN), tumour necrosis factor (TNF) and interleukins IL1β, IL12, IL17 and IL18 in RA synovium obtained by arthroscopy from 34 patients with RA. Monocytes, monocyte-derived dendritic cells (MoDCs) and RA synovial fibroblasts were stimulated via TLR3 (poly-IC) and TLR7 (loxorubin), after which IL1β, IL6 and TNF were measured by Luminex bead array technology. Following preincubation with IFN, IL1β and IL18, TLR3 and TLR7 mRNA expression was assessed using real-time PCR. Cytokine production after preincubation with IFN and subsequent TLR stimulation was measured.

Results: Synovial TLR3/7 expression was co-expressed with IFN, IL1β and IL18, but not with TNF, IL12 and IL17. Stimulation of TLR3/TLR7 on monocytes, MoDCs or synovial fibroblasts led to secretion of type I IFN but no biologically active IL1β or IL18 could be detected. Type I IFN increased TLR3/7 mRNA expression whereas IL1β and IL18 did not. In spite of the fact that the mRNA level of TLR4 remained unchanged, IFN enhanced the response to TLR4 agonists, a phenomenon that was clearly more marked in patients with RA.

Conclusion: Type I interferons are highly co-expressed with TLR3/TLR7 in RA synovium. They enhance TLR3/TLR7-mediated cytokine production and also TLR4-mediated responses.

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