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Phloretin as a Potent Natural TLR2/1 Inhibitor Suppresses TLR2-Induced Inflammation

Department of Bioscience and Biotechnology, Konkuk University, Seoul 05029, Korea
Department of Immunology, School of Medicine, Konkuk University, Chungju 380-701, Korea
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Nutrients 2018, 10(7), 868;
Received: 24 May 2018 / Revised: 22 June 2018 / Accepted: 2 July 2018 / Published: 5 July 2018
PDF [2046 KB, uploaded 5 July 2018]


Toll-like receptor 2 (TLR2) responses are involved in various inflammatory immune disorders. Phloretin is a naturally occurring dietary flavonoid that is abundant in fruit. Here, we investigated whether the anti-inflammatory activity of phloretin is mediated through TLR2 pathways, and whether phloretin acts as an inhibitor of TLR2/1 heterodimerization using the TLR2/1 agonist Pam3CSK4. We tested the effects of phloretin on tumor necrosis factor (TNF)-α production induced by various TLRs using known TLR-specific agonists. Phloretin significantly inhibited Pam3CSK4-induced TRL2/1 signaling in Raw264.7 cells compared to TLR signaling induced by the other agonists tested. Therefore, we further tested the effects of phloretin in human embryonic kidney (HEK) 293-hTLR2 cells induced by Pam3CSK4, and confirmed that phloretin has comparable inhibition of TLR2/1 heterodimerization to that induced by the known TLR2 inhibitor CU-CPT22. Moreover, phloretin reduced the secretion of the inflammatory cytokines TNF-α and interleukin (IL)-8 in Pam3CSK4-induced HEK293-hTLR2 cells, whereas it did not significantly reduce these cytokines under Pam2CSK4-induced activation. Western blot results showed that phloretin significantly suppressed Pam3CSK4-induced TLR2 and NF-κB p65 expression. The molecular interactions between phloretin and TLR2 were investigated using bio-layer interferometry and in silico docking. Phloretin bound to TLR2 with micromolar binding affinity, and we proposed a binding model of phloretin at the TLR2–TLR1 interface. Overall, we confirmed that phloretin inhibits the heterodimerization of TLR2/1, highlighting TLR2 signaling as a therapeutic target for treating TLR2-mediated inflammatory immune diseases. View Full-Text
Keywords: phloretin; dietary flavonoid; inflammation; TLR2; TLR1; inhibitor phloretin; dietary flavonoid; inflammation; TLR2; TLR1; inhibitor

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Kim, J.; Durai, P.; Jeon, D.; Jung, I.D.; Lee, S.J.; Park, Y.-M.; Kim, Y. Phloretin as a Potent Natural TLR2/1 Inhibitor Suppresses TLR2-Induced Inflammation. Nutrients 2018, 10, 868.

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