Green Tea Polyphenol EGCG Upregulates Tollip Expression by Suppressing Elf-1 Expression

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A natural substance in green tea regulates innate immune response

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More than 1,200 years ago, Buddhist monks brought young Chinese green tea trees to Japan. In the late 16th century, the tea ceremony was introduced to Japanese culture, popularizing the idea that drinking the tea was excellent for health. However, green tea has been used for over 5,000 years in traditional Chinese medicine for is curative virtues regarding a wide range of diseases. Modern science recently isolated the active compounds and characterized their exact roles in regulating many biological functions.
In this article, Motofumi Kumazoe deciphers the role of the main polyphenol in green tea, epigallocatechin-3-O-gallate (EGCG), for regulating a specific TLR signaling pathway (TLR-4) in innate immune response. This polyphenol’s complex mechanism of action can be summarized as follows: EGCG suppresses expression of the Elf-1 transcription factor, thus increasing production of the Toll-interacting protein (Tollip) inhibitory adaptor protein of the TLR-4 pathway, leading to down-regulation of TLR-4 mediated signaling and ultimately anti-inflammatory response. Indeed, a complex cascade with many different pieces!
Motofumi placed significant emphasis on studying how Elf-1 expression was inhibited by EGCG. He proved that Protein Phosphatase 2A and the second messenger cGMP were the keys to suppressing Elf-1 expression.
An impressive set of data is presented here to illustrate this cascade of events. In-vitro studies on mouse macrophage RAW264.7 cells were performed using siRNA, Western-blot, immunofluorescence, and direct quantification of both cGMP and IL-6. In-vivo studies on mice treated either with EGCG or cGMP production inducers demonstrate increased Tollip production clearly.
The benefits of green tea were demonstrated on a wide range of diseases, from Type-2 diabetes to Alzheimer’s disease and tumor metastasis. The new role of green tea polyphenols in regulating innate immune response opens new possibilities for effective anti-inflammatory treatments.
When modern science explains and confirms the power of traditional natural medicine… and the incredible benefits of drinking green tea!

Abstract

TLR signaling is critical to innate immune system regulation; however, aberrant TLR signaling is involved in several diseases, including insulin resistance, Alzheimer’s disease, and tumor metastasis. Moreover, a recent study found that TLR-4 signaling pathway inhibition might be a target for the suppression of chronic inflammatory disorders. In this article, we show that the green tea polyphenol epigallocatechin-3-O-gallate (EGCG) increases the expression of Toll interacting protein, a strong inhibitor of TLR4 signaling, by suppressing the expression of E74-like ETS transcription factor 1 (Elf-1). A mechanistic study revealed that EGCG suppressed Elf-1 expression via protein phosphatase 2A/cyclic GMP (cGMP)-dependent mechanisms. We also confirmed that orally administered EGCG and a cGMP inducer upregulated Toll interacting protein expression, increased intracellular levels of cGMP in macrophages, and suppressed Elf-1 expression. These data support EGCG and a cGMP inducer as potential candidate suppressors of TLR4 signaling.

Details

Journal of Immunology. 2017 Nov 1;199(9):3261-3269.

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