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

 

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Abstract

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 (EC₅₀: 0.27 μM). However, resveratrol exhibited a much smaller effect (EC₅₀: 28.37 μM). H1N1 infection increased the time-dependent phosphorylation of the transcription factor STAT₁ and of Akt (a downstream effector protein of PI3K). When the PI3K-Akt pathway was blocked by wortmannin, H1N1-stimulated STAT₁ phosphorylation and RANTES production were both abrogated, demonstrating that the PI3K-Akt pathway is necessary for STAT₁ activation and RANTES production in A549 cells. Furthermore, H1N1-stimulated phosphorylation of Akt and STAT₁ 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 STAT₁-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

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Wen-Fei Chiou, Ph. D.

Division of Basic Chinese Medical Research

National Research Institute of Chinese Medicine

No. 155-1, Sec. 2, Li-Nung St.

Shipai

Taipei 112

Taiwan

R.O.C.

Phone: +886-2-2820199 (4481)

Fax: +886-2-28250743

Email: wfchiou@cma23.nricm.edu.tw