title: Hyaluronan differently modulates TLR-4 and the inflammatory response in mouse chondrocytes.
abstract: Hyaluronic acid (HA) may exert different action depending on its degree of polymerization. Small HA fragments induce proinflammatory responses, while highly polymerized HA exerts a protective effect in inflammatory pathologies such as rheumatoid arthritis. In both cases the toll-like receptor 4 (TLR-4) seems to be involved in the modulation of the inflammation process. The aim of this study was to investigate the influence of short HA oligosaccharides (HA 4-mers) and high molecular weight HA (HMWHA) in the inflammatory response in normal mouse chondrocytes. Messenger RNA and related protein levels were measured for TLR-4, tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), interleukin-6 (IL-6), and interleukin-18 (IL-18) in cells with and without the addition of HA. NF-kB activation was also evaluated. 4-mer HA treatment produced a significant up-regulation of all parameters considered while HMWHA did not exert any activity in untreated cells although it was able to reduce the effects of 4- mers HA significantly. Specific TLR-4 small interference RNA (siRNA) was used to confirm TLR-4 as the target of HA action. This study suggests that HA may modulate proinflammatory cytokines via its different degree of polymerization and inflammatory action may be modulated as a result of the interaction between HA and TLR-4.
authors.affiliation: 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.forename: Giuseppe M
authors.initials: GM
authors.lastname: Campo
authors.forename: Angela
authors.initials: A
authors.lastname: Avenoso
authors.forename: Angela
authors.initials: A
authors.lastname: D'Ascola
authors.forename: Vera
authors.initials: V
authors.lastname: Prestipino
authors.forename: Michele
authors.initials: M
authors.lastname: Scuruchi
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Nastasi
authors.forename: Alberto
authors.initials: A
authors.lastname: Calatroni
authors.forename: Salvatore
authors.initials: S
authors.lastname: Campo
mesh_terms: D000818:Animals; D002358:Cartilage, Articular / Q000166:cytology; D048430:Cell Shape; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects* / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D006820:Hyaluronic Acid / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D016328:NF-kappa B; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D006820:Hyaluronic Acid