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

DOI Web Site PubMed 被引用文献3件 参考文献69件
  • Yasuda Tadashi
    Department of Sports Medicine, Faculty of Budo and Sports Studies, Tenri University, Japan

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  • Hyaluronan Inhibits Akt, Leading to Nuclear Factor-.KAPPA.B Down-Regulation in Lipopolysaccharide-Stimulated U937 Macrophages
  • Hyaluronan inhibits Akt leading to nuclear factor k B down regulation in lipopolysaccharide stimulated U937 macrophages

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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.

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