Hyaluronan Inhibits Akt, Leading to Nuclear Factor-kappa B Down-Regulation in Lipopolysaccharide-Stimulated U937 Macrophages

作者：Yasuda Tadashi^*

来源：Journal of Pharmacological Sciences, 2011, 115(4): 509-515.

DOI：10.1254/jphs.10244FP

• hyaluronan
• Akt
• nuclear factor-kappa B
• lipopolysaccharide
• intercellular adhesion molecule-1

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)-kappa B activation by proinflammatory cytokines and lipopolysaccharide (LPS), intracellular upstream events that cause NF-kappa B 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-kappa B 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-kappa B, whereas HA (1 mg/ml) down-regulated LPS-stimulated phosphorylation of Akt and NF-kappa B. Inhibition studies using LY294002 (20 mu M) revealed the requirement of the PI3K/Akt pathway for LPS-stimulated IL-6 production and NF-kappa B activation. Pretreatment with anti-intercellular adhesion molecule-1 (ICAM-1) antibody (20 mu g/ml) reversed the inhibitory effects of HA on LPS-induced production of IL-6 and activation of Akt and NF-kappa B. Herein, we provided the first evidence that HA suppresses the LPS-activated PI3K/Akt pathway, leading to down-regulation of NF-kappa B with diminished IL-6 production through interaction with ICAM-1

• 出版日期2011-4