Methylxanthines block antigen-induced responses in RBL-2H3 cells independently of adenosine receptors or cyclic AMP: evidence for inhibition of antigen binding to IgE.
Activation of a novel adenosine receptor in a rat tumor mast cell line (RBL-2H3 cells) elicits a transient generation of inositol 1,4,5-trisphosphate and an equally transient increase in the level of free cytosol Ca++: Such responses promote little exocytosis, but markedly enhance the secretory response to antigen. A variety of xanthine adenosine receptor antagonists did not suppress the responses to the adenosine analog 5-N-ethylcarboxamidoadenosine. However, 3-isobutyl-1-methylxanthine (IBMX) and certain related xanthines inhibited antigen (dinitrophenylated bovine serum albumin, DNP-BSA)-induced generation of inositol phosphates, the increase in level of free cytosolic Ca++ and exocytosis in RBL-2H3 cells that were primed with a monoclonal DNP-specific immunoglobulin E (from hybridoma H1 DNP-epsilon-26.82). The same compounds inhibited the binding of antigen to cell attached DNP-specific IgE in a highly selective manner. Incorporation of an aromatic or cycloalkyl group in the 8-position of IBMX or theophylline, for example, resulted in compounds that were more potent inhibitors than the parent compounds. Conversely, substituents in the 7- or 9-position of IBMX resulted in inactive compounds. 1,3-Diethylxanthine and 1,3-dipropylxanthine had no activity, suggesting that substituents as large as ethyl or propyl are not tolerated at the 1-position. Inhibition by IBMX was not observed when cells were activated by nonimmunological stimulants or when cells were primed with certain other monoclonal preparations of DNP-specific IgE and stimulated by DNP-BSA.(ABSTRACT TRUNCATED AT 250 WORDS)
Ali
H
H
Laboratory of Chemical Pharmacology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland.
Müller
C E
CE
Daly
J W
JW
Beaven
M A
MA
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D019830:Adenosine-5'-(N-ethylcarboxamide); D000818:Animals; D000941:Antigens / Q000276:immunology* / Q000378:metabolism; D000242:Cyclic AMP / Q000502:physiology*; D004140:Dinitrophenols / Q000276:immunology / Q000378:metabolism; D007073:Immunoglobulin E / Q000276:immunology / Q000378:metabolism*; D058914:Purinergic Antagonists; D051381:Rats; D011983:Receptors, Purinergic / Q000145:classification; D012710:Serum Albumin, Bovine / Q000276:immunology / Q000378:metabolism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D010738:Type C Phospholipases / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology*
D000941:Antigens; D004140:Dinitrophenols; D058914:Purinergic Antagonists; D011983:Receptors, Purinergic; D014665:Vasodilator Agents; D014970:Xanthines; C034638:dinitrophenyl-bovine serum albumin; D012710:Serum Albumin, Bovine; D019830:Adenosine-5'-(N-ethylcarboxamide); D007073:Immunoglobulin E; D000242:Cyclic AMP; D010738:Type C Phospholipases; D000241:Adenosine; D015056:1-Methyl-3-isobutylxanthine