Epigallocatechin-3-gallate, a green tea-derived polyphenol, inhibits IL-1β-dependent proinflammatory signal transduction in cultured respiratory epithelial cells

Polyphenolic components of green tea, such as epigallocatechin-3-gallate (EGCG), have potent anti-inflammatory properties. We previously showed that EGCG inhibits tumor necrosis factor-alpha (TNF-alpha)-mediated activation of the nuclear factor-kappaB (NF-kappaB) pathway, partly through inhibition of IkappaB kinase (IKK). The NF-kappaB pathway may also be activated in response to interleukin-1beta (IL-1beta) stimulation through a distinct signal transduction pathway. We therefore hypothesized that EGCG inhibits IL-1beta-mediated activation of the NF-kappaB pathway. Because the gene expression of interleukin-8 (IL-8), the major human neutrophil chemoattractant, is dependent on activation of NF-kappaB, IL-8 gene expression in human lung epithelial (A549) cells treated with human IL-1beta was used as a model of IL-1beta signal transduction. The EGCG markedly inhibited IL-1beta-mediated IL-1beta receptor-associated kinase (IRAK) degradation and the signaling events downstream from IRAK degradation: IKK activation, IkappaBalpha degradation, and NF-kappaB activation. In addition, EGCG inhibited phosphorylation of the p65 subunit of NF-kappaB. The functional consequence of this inhibition was evident by inhibition of IL-8 gene expression. Therefore, the green tea polyphenol EGCG is a potent inhibitor of IL-1beta signal transduction in vitro. The proximal mechanisms of this effect involve inhibition of IRAK-dependent signaling and phosphorylation of p65.