O-methylated catechins from tea leaves inhibit multiple protein kinases in mast cells.
Tea contains a variety of bioactive compounds. In this study, we show that two O-methylated catechins, (-)-epigallocatechin-3-O-(3-O-methyl) gallate and (-)-epigallocatechin-3-O-(4-O-methyl) gallate, inhibit in vivo mast cell-dependent allergic reactions more potently than their nonmethylated form, (-)-epigallocatechin-3-O-gallate. Consistent with this, these O-methylated catechins inhibit IgE/Ag-induced activation of mouse mast cells: histamine release, leukotriene release, and cytokine production and secretion were all inhibited. As a molecular basis for the catechin-mediated inhibition of mast cell activation, Lyn, Syk, and Bruton's tyrosine kinase, the protein tyrosine kinases, known to be critical for early activation events, are shown to be inhibited by the O-methylated catechins. In vitro kinase assays using purified proteins show that the O-methylated catechins can directly inhibit the above protein tyrosine kinases. These catechins inhibit IgE/Ag-induced calcium response as well as the activation of downstream serine/threonine kinases such as Akt and c-Jun N-terminal kinase. These observations for the first time have revealed the molecular mechanisms of antiallergic effects of tea-derived catechins.
Maeda-Yamamoto
Mari
M
National Institute of Vegetable and Tea Science, National Agriculture Research Organization, and School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
Inagaki
Naoki
N
Kitaura
Jiro
J
Chikumoto
Takao
T
Kawahara
Hiroharu
H
Kawakami
Yuko
Y
Sano
Mitsuaki
M
Miyase
Toshio
T
Tachibana
Hirofumi
H
Nagai
Hiroichi
H
Kawakami
Toshiaki
T
D000818:Animals; D018926:Anti-Allergic Agents / Q000494:pharmacology*; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008407:Mast Cells / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D008745:Methylation; D051379:Mice; D008808:Mice, Inbred CBA; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010323:Passive Cutaneous Anaphylaxis / Q000187:drug effects; D018515:Plant Leaves / Q000737:chemistry; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D064546:Protein Kinase C beta; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013662:Tea / Q000737:chemistry*
D018926:Anti-Allergic Agents; D004791:Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; D013662:Tea; D002392:Catechin; C045651:epigallocatechin gallate; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D019950:Mitogen-Activated Protein Kinase 1; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases