title: Hyaluronan reduces inflammation in experimental arthritis by modulating TLR-2 and TLR-4 cartilage expression.
abstract: Previous studies have reported that low molecular mass HA and highly polymerized HA respectively elicited pro- and anti-inflammatory responses by modulating the toll-like receptor 4 (TLR-4) and the TLR-2. The activation of TLR-4 and TLR-2 mediated by collagen-induced arthritis (CIA) induces the myeloid differentiation primary response protein (MyD88) and the tumor necrosis factor receptor-associated factor 6 (TRAF6), and ends with the liberation of NF-kB which, in turn, stimulates pro-inflammatory cytokine production. The aim of this study was to investigate the influence of high molecular weight HA at different concentrations on TLR-4 and TLR-2 modulation in CIA in mice. Arthritis was induced in mice via intradermal injection of an emulsion containing bovine type II collagen in complete Freund's adjuvant. Mice were treated with HA intraperitoneally daily for 30days. CIA increased TLR-4, TLR-2, MyD88 and TRAF6 mRNA expression and the related protein in the cartilage of arthritic joints. High levels of both mRNA and related protein were also detected for tumor necrosis factor alpha (TNF-α), interleukin 1-beta (IL-1-β), interleukin-17 (IL-17), matrix metalloprotease-13 (MMP-13) and inducible nitric oxide synthase (iNOS) in the joint of arthritic mice. HA treatment significantly limited CIA incidence and decreased all the parameters up-regulated by CIA. The improvement of biochemical parameters was also supported by histological analysis, plasma and synovial fluid HA levels. These results suggest that the TLR-4 and TLR-2 play an important role in the arthritis mechanism and the interaction/block of HA at high molecular mass may reduce inflammation and cartilage injury.
authors: Department of Biochemical, Physiological and Nutritional Sciences, Section of Medical Chemistry, School of Medicine, University of Messina, Policlinico Universitario, 98125 Messina, Italy. gcampo@unime.it
authors: Giuseppe M
authors: GM
authors: Campo
authors: Angela
authors: A
authors: Avenoso
authors: Giancarlo
authors: G
authors: Nastasi
authors: Antonio
authors: A
authors: Micali
authors: Vera
authors: V
authors: Prestipino
authors: Mario
authors: M
authors: Vaccaro
authors: Angela
authors: A
authors: D'Ascola
authors: Alberto
authors: A
authors: Calatroni
authors: Salvatore
authors: S
authors: Campo
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000473:pathology*; D002356:Cartilage / Q000187:drug effects / Q000378:metabolism*; D024043:Collagen Type II; D006820:Hyaluronic Acid / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D007249:Inflammation / Q000276:immunology / Q000473:pathology*; D051379:Mice; D008811:Mice, Inbred DBA; D008970:Molecular Weight; D053594:Myeloid Differentiation Factor 88 / Q000096:biosynthesis; D016328:NF-kappa B / Q000378:metabolism; D013582:Synovial Fluid / Q000737:chemistry; D048029:TNF Receptor-Associated Factor 6 / Q000096:biosynthesis; D051195:Toll-Like Receptor 2 / Q000096:biosynthesis*; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis*
chemical_list: D024043:Collagen Type II; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D048029:TNF Receptor-Associated Factor 6; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D006820:Hyaluronic Acid