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FLAVONOIDS DIFFERENTIALLY REGULATE IFN-GAMMA-INDUCED ICAM-1 EXPRESSION IN HUMAN KERATINOCYTES: MOLECULAR MECHANISMS OF ACTION.

Bito1,4, T., Roy2, S., Sen2, C.K., Shirakawa3, T., Gotoh3, A., Ueda4, M., Ichihashi4, M., Packer1,5, L. 1 Department of Molecular and Cell Biology, University of California, Berkeley, CA, 2Laboratory of Molecular Medicine, Davis Heart and Lung Research Institute, The Ohio State University Medical Center, Columbus, OH , 3Department of Urology, Kobe University Graduate School of Medicine, Japan, 4Department of Dermatology, Kobe University Graduate School of Medicine, Japan, 5Department of Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California, Los Angeles, CA.
Abstract

The effect of plant flavonoids on intercellular adhesion molecule-1 (ICAM-1) expression in human keratinocyte was investigated. ICAM-1 is known to mediate skin inflammation. Among the flavonoids tested, taxifolin was the most potent in inhibiting interferon Îł (IFN Îł)-induced ICAM-1 protein as well as mRNA expression in human keratinocytes. Much smaller dosages of taxifolin were required in primary keratinocytes compared to HaCaT (immortalized cell) to achieve similar levels of inhibition in the inducible ICAM-1 expression. Regulation of inducible ICAM-1 expression by taxifolin was at transcriptional level by inhibiting the activation of signal transducers and activators of transcription (STAT)1 and protein tyrosine phosphorylation of Janus kinase (JAK)1 suggesting that the JAK-STAT pathway may be the molecular site of action of taxifolin. Finally, taxifolin pre-treatment also potently inhibited IFNÎł-induced ICAM-1 expression in a reconstructed human skin equivalent suggesting therapeutic potential of taxifolin in skin pathological conditions related to increased cell adhesion and inflammation.

Keywords

Anti-histamines, Cell adhesion, Corticosteroid, EpiDerm, Flavonoids, ICAM-1, IFN-gamma, Immunologic reactions, Immunosuppressant, Inflammation, Intercellular adhesion molecule-1 (ICAM-1), Interferon gamma, Leukocytes, Reconstructed human skin, Signal transducers and activators of transcription 1, Skin inflammation, T-Cells, Taxifolin, Tissue repair, Tyrosine kinase activation, UVB

Materials Tested

Anthocyanidins, Apigenin, Catechin, Epicatechin, Ferulic acid, Flavonol, Interferon gamma (IFN-gamma), Phenyl propanoids, Quercetin, Taxifolin

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