Adenosine A2A receptor activation and hyaluronan fragment inhibition reduce inflammation in mouse articular chondrocytes stimulated with interleukin-1β.

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-kappa B, 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)-1 beta. IL-1 beta 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-kappa B activation was also associated with increased levels of inflammatory cytokines, including tumor necrosis factor-a 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-1 beta. These results suggest that the inflammatory response may be reduced either by blocking oligosaccharides from HA degradation or by A(2A)R stimulation.