title: 4-mer hyaluronan oligosaccharides stimulate inflammation response in synovial fibroblasts in part via TAK-1 and in part via p38-MAPK.
abstract: 4-mer hyaluronan (HA) oligosaccharides stimulate pro-inflammatory effects in different cell types by interacting with both the toll-like receptor-4 (TLR-4) and -2 (TLR-2). This interaction induces the activation of the transforming growth factor activated kinase-1 (TAK-1) that activates the nuclear factor kappaB (NF-kB) either directly and/or through the activation of p38-mitogen-activated protein kinase (p38-MAPK). This in turn induces the transcription of proinflammatory mediators that prime inflammation. Our aim was to investigate the involvement of TAK-1 and p38-MAPK in 4-mer HA oligosaccharide-induced inflammatory response in mouse synovial fibroblasts obtained from normal DBA/J1 mice (NSF) and from mice subjected to collagen-induced arthritis (CIA). Treatment of NSF and rheumatoid arthritis synovial fibroblasts (RASF) with 4-mer HA showed a marked up-regulation of TLR-4, TLR-2, TAK-1 and p38-MAPK mRNA expression and of the related proteins, as well as NF-kB activation. High levels were also detected of TNF-α, IL- 1β, MMP-13 and iNOS. Treatment of NSF and RASF, previously stimulated with 4-mer HA oligosaccharides, with TAK- 1 and/or p38-MAPK specific inhibitors significantly reduced all the parameters, although the inhibitory effect of p38- MAPK was less effective than that of TAK-1. The addition of CD44 antibody to both NSF and RASF showed that CD44 was not involved in 4-mer HA-induced inflammation.
authors.affiliation: Department of Biomedical Sciences and Morphological and Functional Images, School of Medicine, University of Messina, Policlinico Universitario, Torre Biologica, 5° piano, Via C. Valeria - 98125 - Messina, Italy. gcampo@unime.it
authors.forename: G M
authors.initials: GM
authors.lastname: Campo
authors.forename: A
authors.initials: A
authors.lastname: Avenoso
authors.forename: A
authors.initials: A
authors.lastname: D'Ascola
authors.forename: V
authors.initials: V
authors.lastname: Prestipino
authors.forename: M
authors.initials: M
authors.lastname: Scuruchi
authors.forename: G
authors.initials: G
authors.lastname: Nastasi
authors.forename: A
authors.initials: A
authors.lastname: Calatroni
authors.forename: S
authors.initials: S
authors.lastname: Campo
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D005347:Fibroblasts / Q000276:immunology* / Q000378:metabolism; D018960:Hyaluronan Receptors / Q000276:immunology; D006820:Hyaluronic Acid / Q000276:immunology*; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000276:immunology*; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000276:immunology; D051379:Mice; D008811:Mice, Inbred DBA; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics; D013583:Synovial Membrane / Q000166:cytology; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000276:immunology*; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D018960:Hyaluronan Receptors; D006820:Hyaluronic Acid; D053583:Interleukin-1beta; D020930:MAP Kinase Kinase Kinases; D053509:Matrix Metalloproteinase 13; D016328:NF-kappa B; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7