The effects of S1319, a novel marine sponge-derived beta2-adrenoceptor agonist, on IgE-mediated activation of human cultured mast cells.
OBJECTIVE
This study aimed to evaluate the ability of S1319 (4-hydroxy-7-[1-(1-hydroxy-2-methylamino) ethyl]-1,3-benzothiazol-2(3H)-one acetate), a novel beta2-adrenoceptor selective agonist derived from marine sponge, to inhibit IgE-mediated activation of human cultured mast cells (HCMC) in vitro.


METHODS
We examined the effect of S1319 (racemate) on tryptase release and tumor necrosis factor-alpha (TNF-alpha) production in HCMC generated from human cord blood cells, after cross-linking of high affinity immunoglobulin E receptors (FcepsilonRI), compared with those of the nonselective beta-adrenoceptor agonist, isoproterenol (R-isomer), the selective beta2-adrenoceptor agonist, salbutamol (racemate), and the selective and long-acting beta2-adrenoceptor agonist, formoterol (racemate). We also evaluated the effect of S1319 on the intracellular cAMP level, inositol phosphate production and protein tyrosine phosphorylation in HCMC.


RESULTS
S1319 and beta-adrenoceptor agonists inhibited the IgE-mediated release of tryptase. Approximate IC50 values of S1319, formoterol, isoproterenol and albuterol for the inhibition of tryptase release were 0.51+/-0.12, 0.15+/-0.1, 0.80+/-0.09, and 28+/-32.4 nM, respectively. S1319 and beta-adrenoceptor agonists also inhibited TNF-alpha production by HCMC in a concentration-dependent manner. Approximate IC50 values of S1319, formoterol and isoproterenol for the inhibition of TNF-alpha production were 0.19+/-0.03, 0.28+/-0.02 and 0.32+/-0.03 nM, respectively. S1319 caused a concentration-dependent increase in total cell cyclic AMP levels in HCMC. On the other hand, S1319 inhibited the accumulation of inositol 1,4,5-triphosphate and IgE-mediated protein tyrosine phosphorylation of 42-kDa protein, p42 mitogen activated protein (MAP) kinase (ERK-2).


CONCLUSIONS
These results indicate that S 1319 and beta-adrenoceptor agonists are potent inhibitors of the IgE-mediated release of mediators from HCMC.
Suzuki
H
H
Pharmaceutical Research Laboratory, Kirin Brewery Co. Ltd., Gunma, Japan. su-hidefumi@kirin.co.jp
Ueno
A
A
Takei
M
M
Shindo
K
K
Higa
T
T
Fukamachi
H
H
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000420:Albuterol / Q000494:pharmacology; D052160:Benzothiazoles; D002478:Cells, Cultured; D053818:Chymases; D003432:Cross-Linking Reagents; D000242:Cyclic AMP / Q000378:metabolism; D004983:Ethanolamines / Q000494:pharmacology*; D000068759:Formoterol Fumarate; D006801:Humans; D007073:Immunoglobulin E / Q000502:physiology*; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D008407:Mast Cells / Q000276:immunology* / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D010766:Phosphorylation; D012697:Serine Endopeptidases / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*; D053802:Tryptases; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
C120088:4-hydroxy-7-(1-(1-hydroxy-2-methylamino)ethyl)-1,3-benzothiazole-2(3H)-one; D000318:Adrenergic beta-Agonists; D052160:Benzothiazoles; D003432:Cross-Linking Reagents; D004983:Ethanolamines; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha; D007073:Immunoglobulin E; D015544:Inositol 1,4,5-Trisphosphate; D000242:Cyclic AMP; D019950:Mitogen-Activated Protein Kinase 1; D012697:Serine Endopeptidases; C083294:chymase 2; D053818:Chymases; D053802:Tryptases; D007545:Isoproterenol; D000420:Albuterol; D000068759:Formoterol Fumarate