Inhibitory effect of xanthones isolated from the pericarp of Garcinia mangostana L. on rat basophilic leukemia RBL-2H3 cell degranulation.
Mangostin, Garcinia mangostana L. is used as a traditional medicine in southeast Asia for inflammatory and septic ailments. Hitherto we indicated the anticancer activity induced by xanthones such as alpha-, beta-, and gamma-mangostin which were major constituents of the pericarp of mangosteen fruits. In this study, we examined the effect of xanthones on cell degranulation in rat basophilic leukemia RBL-2H3 cells. Antigen (Ag)-mediated stimulation of high affinity IgE receptor (FcepsilonRI) activates intracellular signal transductions resulting in the release of biologically active mediators such as histamine. The release of histamine and other inflammatory mediators from mast cell or basophils is the primary event in several allergic responses. These xanthones suppressed the release of histamine from IgE-sensitized RBL-2H3 cells. In order to reveal the inhibitory mechanism of degranulation by xanthones, we examined the activation of intracellular signaling molecules such as Lyn, Syk, and PLCgammas. All the xanthones tested significantly suppressed the signaling involving Syk and PLCgammas. In Ag-mediated activation of FcepsilonRI on mast cells, three major subfamilies of mitogen-activated protein kinases were activated. The xanthones decreased the level of phospho-ERKs. Furthermore, the levels of phospho-ERKs were observed to be regulated by Syk/LAT/Ras/ERK pathway rather than PKC/Raf/ERK pathway, suggesting that the inhibitory mechanism of xanthones was mainly due to suppression of the Syk/PLCgammas/PKC pathway. Although intracellular free Ca(2+) concentration ([Ca(2+)](i)) was elevated by FcepsilonRI activation, it was found that alpha- or gamma-mangostin treatment was reduced the [Ca(2+)](i) elevation by suppressed Ca(2+) influx.
Itoh
Tomohiro
T
Gifu International Institute of Biotechnology, Bio-active Substances Research, 1-1 Naka-Fudogaoka, Kakamigahara, Gifu 504-0838, Japan. titoh@giib.or.jp
Ohguchi
Kenji
K
Iinuma
Munekazu
M
Nozawa
Yoshinori
Y
Akao
Yukihiro
Y
D000818:Animals; D002118:Calcium / Q000378:metabolism; D015550:Cell Degranulation / Q000187:drug effects*; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D029762:Garcinia mangostana / Q000737:chemistry*; D006632:Histamine / Q000378:metabolism; D007073:Immunoglobulin E / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D015471:Leukemia, Basophilic, Acute / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D020935:MAP Kinase Signaling System; D015394:Molecular Structure; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051966:Phospholipase C gamma / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D017455:Receptors, IgE / Q000378:metabolism; D013329:Structure-Activity Relationship; D000072377:Syk Kinase; D044004:Xanthones / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*
D047908:Intracellular Signaling Peptides and Proteins; D017382:Reactive Oxygen Species; D017455:Receptors, IgE; D044004:Xanthones; D007073:Immunoglobulin E; D006632:Histamine; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606898:Syk protein, rat; D048049:Extracellular Signal-Regulated MAP Kinases; D051966:Phospholipase C gamma; D002118:Calcium