(+)-Vitisin A Inhibits Influenza A Virus-Induced RANTES Production in A549 Alveolar Epithelial Cells through Interference with Akt and STAT1 Phosphorylation

Airway epithelial cells are the initial sites of influenza virus infection. They participate in the airway inflammatory response by expressing various chemokines such as regulated on activation, normal T cell expressed and secreted (RANTES). In the present investigation, the effects of five stilbenes previously isolated from the roots of Vitis thunbergii on RANTES produced by influenza A virus (H1N1)-infected A549 alveolar epithelial cells were studied. We identified (+)-vitisin A, a tetramer of resveratrol, as a potent agent that inhibits RANTES secretion (EC 50 : 0.27 μM). However, resveratrol exhibited a much smaller effect (EC 50 : 28.37 μM). H1N1 infection increased the time-dependent phosphorylation of the transcription factor STAT 1 and of Akt (a downstream effector protein of PI3K). When the PI3K-Akt pathway was blocked by wortmannin, H1N1-stimulated STAT 1 phosphorylation and RANTES production were both abrogated, demonstrating that the PI3K-Akt pathway is necessary for STAT 1 activation and RANTES production in A549 cells. Furthermore, H1N1-stimulated phosphorylation of Akt and STAT 1 were also significantly attenuated by (+)-vitisin A. These results suggested that (+)-vitisin A might be a potent anti-inflammatory agent that inhibits influenza A virus-induced RANTES production by interfering with Akt- and STAT 1 -related signal pathways. Abbreviations CCL:CC chemokine ligand ERK:extracellular signal-regulated kinase IFN-γ:interferon-γ Jak:Janus kinase MCP-1:monocyte chemoattractant protein-1 NF-κB:nuclear factor-κB NP-40:nonylphenoxy(polyethoxy)ethanol Pl3K-Akt:phosphatidylinositol-3-kinase (Pl3K)-Akt PMSF:phenylmethylsulfonyl fluoride RANTES:regulated on activation, normal T cell expressed and secreted SDS:lauryl sulfate sodium salt STAT:signal transducer and activator of transcription