title: Epigallocatechin-3-gallate induces cytokine production in mast cells by stimulating an extracellular superoxide-mediated calcium influx.
abstract: The green tea polyphenol (-)-epigallocatechin-3-O-gallate (EGCG) has various biological activities, including anti-inflammatory, anti-neoplastic, anti- and pro-apoptotic, and neuroprotective effects. Although these are often associated with increased intracellular reactive oxygen species (ROS) and Ca(2+) levels, their involvement in biological effects is poorly understood. Here we report that EGCG induces cytokine production in mast cells via Ca(2+) influx and ROS generation. EGCG at concentrations of ≥50 μM induced interleukin-13 and tumor necrosis factor-α production in RBL-2H3 and bone marrow-derived mast cells. The effects were dependent on extracellular Ca(2+), and EGCG induced Ca(2+) release from intracellular stores and Ca(2+) influx. Ca(2+) influx was suppressed by 2-aminoethoxydiphenyl borate, an inhibitor of store-operated Ca(2+) (SOC) channels, including Ca(2+) release-activated Ca(2+) channels and transient receptor potential canonical channels. EGCG failed to induce Ca(2+) influx through SOC channels. EGCG-activated Ca(2+) channels were genetically and pharmacologically distinct from Ca(v)1.2 L-type Ca(2+) channels, another route of Ca(2+) influx into mast cells. EGCG evoked release of superoxide (O(2)(·-)) into the extracellular space. Exogenous superoxide dismutase, but not catalase, inhibited EGCG-evoked Ca(2+) influx and cytokine production, indicating that extracellular O(2)(·-) regulates these events. EGCG can serve as a powerful tool for studying O(2)(·-)-regulated Ca(2+) channels, which may be selectively involved in the regulation of cytokine production but have yet to be elucidated.
authors.affiliation: Division of Molecular Cell Immunology and Allergology, Nihon University Graduate School of Medical Science, Tokyo, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Inoue
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Chisei
authors.initials: C
authors.lastname: Ra
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D015550:Cell Degranulation / Q000187:drug effects; D045744:Cell Line, Tumor; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects*; D008407:Mast Cells / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D051381:Rats; D013481:Superoxides / Q000378:metabolism*
chemical_list: D016207:Cytokines; D013481:Superoxides; D002392:Catechin; C045651:epigallocatechin gallate; D002118:Calcium