Cocoa polyphenols suppress TNF-α-induced vascular endothelial growth factor expression by inhibiting phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase kinase-1 (MEK1) activities in mouse epidermal cells

Cocoa polyphenols have antioxidant and anti-inflammatory effects. TNF-alpha is a pro-inflammatory cytokine that has a vital role in the pathogenesis of inflammatory diseases such as cancer and psoriasis. Vascular endothelial growth factor (VEGF) expression is associated with tumorigenesis, CVD, rheumatoid arthritis and psoriasis. We tested whether cocoa polyphenol extract (CPE) inhibited TNF-alpha-induced VEGF expression in promotion-sensitive JB6 mouse epidermal cells. CPE significantly inhibited TNF-alpha-induced up-regulation of VEGF via reducing TNF-alpha-induced activation of the nuclear transcription factors activator protein-1 (AP-1) and NF-kappa B, which are key regulators of VEGF expression. CPE also inhibited TNF-alpha-induced phosphorylation of protein kinase B (Akt) and extracellular signal-regulated kinase. CPE blocked activation of their downstream kinases, p70 kDa ribosomal protein S6 kinase and p90 kDa ribosomal protein S6 kinase. CPE suppressed phosphoinositide 3-kinase (PI3K) activity via binding PI3K directly. CPE did not affect TNF-alpha-induced phosphorylation of mitogen-activated protein kinase kinase-1 (MEK1) but suppressed TNF-alpha-induced MEK1 activity. Collectively, these results indicate that CPE reduced TNF-alpha-induced up-regulation of VEGF by directly inhibiting PI3K and MEK1 activities, which may contribute to its chemopreventive potential.