title: Local interleukin-1-driven joint pathology is dependent on toll-like receptor 4 activation.
abstract: Toll-like receptors (TLRs) may contribute to the pathogenesis of chronic inflammatory destructive diseases through the recognition of endogenous ligands produced on either inflammation or degeneration of the extracellular matrix. The presence of endogenous TLR agonists has been reported in rheumatoid joints. In the present study, we investigated the significance of TLR2 and TLR4 activation by locally- produced endogenous ligands in the severity of joint inflammation and destruction. Local joint pathology independent of systemic immune activation was induced by overexpression of interleukin (IL)-1 and TNF in naive joints using adenoviral gene transfer. Here, we report that at certain doses, IL-1-induced local joint inflammation, cartilage proteoglycan depletion, and bone erosion are dependent on TLR4 activation, whereas TLR2 activation is not significantly involved. In comparison, tumor necrosis factor alpha-driven joint pathology seemed to be less dependent on TLR2 and TLR4. The severity of IL-1-induced bone erosion and irreversible cartilage destruction was markedly reduced in TLR4(-/-) mice, even though the degree of inflammation was similar, suggesting uncoupled processes. Furthermore, the expression of cathepsin K, a marker for osteoclast activity, induced by IL-1beta was dependent on TLR4. Overexpression of IL-1beta in the joint as well as ex vivo IL-1 stimulation of patellae provoked the release of endogenous TLR4 agonists capable of inducing TLR4-mediated cytokine production. These data emphasize the potential relevance of TLR4 activation in rheumatoid arthritis, particularly with respect to IL-1-mediated joint pathology.
authors.affiliation: Department of Rheumatology, Radboud University Nijmegen Medical Centre, The Netherlands. s.abdollahi-roodsaz@reuma.umcn.nl
authors.forename: Shahla
authors.initials: S
authors.lastname: Abdollahi-Roodsaz
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
authors.forename: Marije I
authors.initials: MI
authors.lastname: Koenders
authors.forename: Ben T
authors.initials: BT
authors.lastname: van den Brand
authors.forename: Fons A J
authors.initials: FA
authors.lastname: van de Loo
authors.forename: Wim B
authors.initials: WB
authors.lastname: van den Berg
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000473:pathology; D002358:Cartilage, Articular / Q000166:cytology / Q000276:immunology / Q000473:pathology; D016207:Cytokines / Q000276:immunology; D007375:Interleukin-1 / Q000276:immunology*; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology; D007719:Knee Joint / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000235:genetics / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
chemical_list: D016207:Cytokines; D007375:Interleukin-1; D053583:Interleukin-1beta; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha