Enhancement of allergic responses in vivo and in vitro by butylated hydroxytoluene.
The effect of butylated hydroxytoluene (BHT), which is used widely as an antioxidant, on IgE-dependent allergic responses in vivo and in vitro was investigated. For in vivo study, passive cutaneous anaphylaxis (PCA) was elicited in rats by i.d. injection of anti-DNP IgE and 48 h later by i.v. injection of DNP-HSA. BHT was i.p. given immediately after anti-DNP IgE injection. For in vitro studies, the rat mast cell line RBL2H3 sensitized with monoclonal anti-dinitrophenol (DNP) IgE was challenged with the multivalent antigen DNP-human serum albumin (DNP-HSA) in the presence or absence of BHT. beta-Hexosaminidase and histamine released from RBL2H3 cells, as indicators of degranulation of the cells, the concentration of intracellular Ca2+, the level of phosphorylated-Akt, and global tyrosine phosphorylation as indicators of mast cell activation, were measured. The results showed that BHT given to anti-DNP IgE-sensitized rats augmented DNP-specific PCA in a dose-dependent manner. In the presence of BHT, IgE-induced releases of beta-hexosaminidase and histamine from RBL2H3 cells were increased. BHT also further elevated IgE-mediated increased concentrations of intracellular Ca2+ and the levels of phosphorylated-Akt, but did not affect global tyrosine phosphorylation, in RBL2H3 cells. Moreover, the PI3K inhibitor LY294002 inhibited IgE-dependent degranulation and its enhancement by BHT. These findings indicate that BHT may upregulate PCA by enhancing mast cell degranulation associated with enhancements of intracellular Ca2+ concentration and PI3K activation, suggesting that BHT might affect allergic diseases such as allergic rhinitis and asthma.
Yamaki
Kouya
K
Department of Pharmacology, Kobe Pharmaceutical University, Kobe, Hyogo 658-8558, Japan.
Taneda
Shinji
S
Yanagisawa
Rie
R
Inoue
Ken-ichiro
K
Takano
Hirohisa
H
Yoshino
Shin
S
D000818:Animals; D000975:Antioxidants / Q000633:toxicity; D002084:Butylated Hydroxytoluene / Q000633:toxicity*; D002118:Calcium / Q000032:analysis / Q000378:metabolism; D015550:Cell Degranulation / Q000187:drug effects; D045744:Cell Line, Tumor; D004140:Dinitrophenols / Q000737:chemistry / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D006636:Histamine Release / Q000187:drug effects; D006967:Hypersensitivity / Q000209:etiology* / Q000378:metabolism; D007424:Intracellular Fluid / Q000737:chemistry / Q000187:drug effects; D015759:Ionomycin / Q000633:toxicity; D007476:Ionophores / Q000633:toxicity; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017455:Receptors, IgE / Q000378:metabolism; D013997:Time Factors; D014443:Tyrosine / Q000378:metabolism; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism
D000975:Antioxidants; D002084:Butylated Hydroxytoluene; D002118:Calcium; D004140:Dinitrophenols; D015759:Ionomycin; D007476:Ionophores; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D017455:Receptors, IgE; D014443:Tyrosine; D001619:beta-N-Acetylhexosaminidases