title: Adenosine A2A receptor activation and hyaluronan fragment inhibition reduce inflammation in mouse articular chondrocytes stimulated with interleukin-1β.
abstract: Small hyaluronan (HA) fragments produced from native HA during inflammation contribute greatly to cell injury in many pathologies. HA oligosaccharides increase proinflammatory cytokine levels by activating both CD44 and toll-like receptor (TLR)-4. Stimulation of CD44 and TLR-4 then activates nuclear factor-κB, which induces the production of proinflammatory cytokines. The adenosine 2A receptor (A(2A)R) is also involved in several inflammation pathologies, and the nucleoside adenosine acts as a potent endogenous inhibitor of inflammation in various tissues by interacting with this receptor. The aim of this study was to investigate the effects of an HA-blocking peptide that inhibits the proinflammatory action of HA oligosaccharides produced during inflammation, together with a specific A(2A)R agonist in a model of normal mouse articular chondrocytes stimulated with interleukin (IL)-1β. IL-1β stimulation significantly increased mRNA expression and the related protein production of TLR-4, TLR-2, CD44 and A(2A)R in articular chondrocytes. The induced nuclear factor-κB activation was also associated with increased levels of inflammatory cytokines, including tumor necrosis factor-α and IL-6, and other inflammatory mediators, such as matrix metalloprotease-13 and inducible nitric oxide synthase. Treatment of chondrocytes with the HA-blocking peptide Pep-1 and/or a specific A(2A)R agonist (CGS-21680) significantly reduced all of the inflammatory parameters upregulated by IL-1β. These results suggest that the inflammatory response may be reduced either by blocking oligosaccharides from HA degradation or by A(2A)R stimulation.
authors.affiliation: Department of Biochemical, Physiological and Nutritional Sciences, Section of Medical Chemistry, School of Medicine, University of Messina, Policlinico Universitario, 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: Michele
authors.initials: M
authors.lastname: Scuruchi
authors.forename: Vera
authors.initials: V
authors.lastname: Prestipino
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: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D058908:Adenosine A2 Receptor Agonists / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects* / Q000378:metabolism*; D018960:Hyaluronan Receptors / Q000378:metabolism; D006820:Hyaluronic Acid / Q000737:chemistry*; D053583:Interleukin-1beta / Q000494:pharmacology*; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D051379:Mice; D052247:Nitric Oxide Synthase Type II; D009844:Oligosaccharides / Q000737:chemistry / Q000494:pharmacology*; D010627:Phenethylamines / Q000494:pharmacology; D043683:Receptors, Adenosine A2 / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D058908:Adenosine A2 Receptor Agonists; D018960:Hyaluronan Receptors; D053583:Interleukin-1beta; D015850:Interleukin-6; D009844:Oligosaccharides; D010627:Phenethylamines; D043683:Receptors, Adenosine A2; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D006820:Hyaluronic Acid; D052247:Nitric Oxide Synthase Type II; D053509:Matrix Metalloproteinase 13; D000241:Adenosine