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TLR-4 Induced Fc[gamma]R expression potentiates early onset of joint inflammation and cartilage destruction during immune complex arthritis: tlr4 largely regulates Fc[gamma]R expression by IL-10.
  1. P LEM van Lent (p.vanlent{at}reuma.umcn.nl)
  1. Radboud UMC Nijmegen, Netherlands
    1. A B Blom (a.blom{at}reuma.umcn.nl)
    1. Radboud UMC Nijmegen, Netherlands
      1. L Grevers (l.grevers{at}reuma.umcn.nl)
      1. Radboud UMC Nijmegen, Netherlands
        1. A Sloetjes (a.sloetjes{at}reuma.umcn.nl)
        1. Radboud UMC Nijmegen, Netherlands
          1. W B van den Berg (w.vandenberg{at}reuma.umcn.nl)
          1. Radboud UMC Nijmegen, Netherlands

            Abstract

            Objective: To study the role of TLR2 and 4 in onset of joint inflammation and cartilage destruction during immune complex mediated arthritis (ICA) and its relation with Fc[gamma]R expression.

            Methods: ICA was induced in knee joints of TLR2- /- and TLR4-/- mice and their wildtype controls. Joint inflammation and cartilage destruction was measured in the knee joint using histology. mRNA levels were determined in synovial specimen and macrophages using Q- PCR and cytokine protein levels in synovial washouts using Bioplex.

            Results:Joint inflammation and cartilage destruction was not different in arthritic TLR2-/- and WT mice. In contrast at day 1 after ICA induction, joint swelling and PG depletion in knee joints of TLR4-/- mice was significantly lower ( inflammation 68-79% and PG depletion 27-76%), when compared to WT controls. Cytokine production at this time-point was markedly reduced in TLR4-/- mice ( IL-1, IL-6, MIP-1a and KC with 49%,72%,68% and 84% respectively). In arthritic synovia of TLR4-/- but also after injection of the antigen PLL- lysozyme alone, mRNA levels of Fc[gamma]R but also the FcgR regulating cytokine IL-10 were significantly lower. Stimulation of peritoneal macrophages with PLL-lys up- regulated mRNA levels of Fc[gamma]R and IL-10 whereas neutralisation by anti-IL-10 antibodies largely blocked FcgR upregulation. At day 4 joint inflammation and cartilage destruction was comparable in TLR4-/- and WT controls.

            Conclusions:TLR 4 regulates early onset of joint inflammation and cartilage destruction during immune complex mediated arthritis by upregulation of Fc[gamma]R expression and enhanced cytokine production. TLR4 mediated up-regulation of Fc[gamma]R is largely mediated by IL-10.

            • Fcgamma receptors
            • cartilage destruction
            • experimental arthritis
            • joint inflammation
            • toll-like receptors

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