Hyaluronan inhibits akt,leading to nuclear factor-κB down-regulation in lipopolysaccharide-stimulated U937 macrophages

Hyaluronan (ha) of high molecular weight is used in the treatment of osteoarthritis and rheumatoid arthritis by intra-articular injection. while ha has been shown to suppress nuclear factor (nf)-κb activation by proinflammatory cytokines and lipopolysaccharide (lps),intracellular upstream events that cause nf-κb down-regulation in response to ha remain unclear. thus,this study was performed to investigate the involvement of phosphoinositide-3-oh kinase (pi3k)/akt in the inhibition of the lps-activated nf-κb pathway by ha in u937 macrophages. in adherent u937 macrophage cultures,pretreatment with ha of 2700 kda (1 mg/ml,1 h) significantly inhibited interleukin-6 (il-6) production by lps (200 ng/ml,24 h)-stimulated u937 cells. lps (200 ng/ml) activated akt and nf-κb,whereas ha (1 mg/ml) down-regulated lps-stimulated phosphorylation of akt and nf-κb. inhibition studies using ly294002 (20 μm) revealed the requirement of the pi3k/akt pathway for lps-stimulated il-6 production and nf-κb activation. pretreatment with anti-intercellular adhesion molecule-1 (icam-1) antibody (20 μg/ml) reversed the inhibitory effects of ha on lps-induced production of il-6 and activation of akt and nf-κb. herein,we provided the first evidence that ha suppresses the lps-activated pi3k/akt pathway,leading to down-regulation of nf-κb with diminished il-6 production through interaction with icam-1. © the japanese pharmacological society.