Ro 19-3704 directly inhibits immunoglobulin E-dependent mediator release by a mechanism independent of its platelet-activating factor antagonist properties.
Rat basophilic leukemia (RBL 2H3) cells were passively sensitized by exposure to monoclonal anti-trinitrophenol mouse immunoglobulin E (anti-trinitrophenol IgE) (0.5 microgram/ml) and triggered by exposure to a sub-optimal concentration of trinitrophenol ovalbumin conjugate (5 ng/ml). At this concentration, trinitrophenol-ovalbumin increased histamine release from a basal rate of 4.8 +/- 0.5 to 28.5 +/- 4.6% and peptidoleukotrienes from less than 0.1 to 4.2 +/- 1.3 ng/10(6) cells in the activated cells. Ro 19-3704 and Ro 19-1400, platelet activating factor (PAF) antagonists which are structural analogs of PAF, potently inhibited both the IgE-dependent release of histamine (IC50 values of 3.0 and 3.6 microM, respectively) and LT release (IC50 values of 5.0 microM for both compounds) from the cells. These effects appeared to be independent to the ability of the compounds to act as PAF antagonists since PAF on its own had no effect on mediator release, and WEB 2086 and BN 52021, structurally distinct PAF antagonists, were relatively ineffective as inhibitors of mediator release. Ro 19-3704 and Ro 19-1400 were observed to be potent inhibitors of the soluble phospholipase A2 activity in synovial fluid from rheumatoid arthritic patients (IC50 values of 6.5 and 8.4 microM, respectively). In contrast, WEB 2086 and BN 52021 had no effect on this phospholipase A2. Ro 19-3704 significantly inhibited the IgE-dependent formation of inositol phosphates in RBL 2H3 cells (IC50 value of 7.0 microM). These data suggest that the mediator release inhibitory action of these compounds may be related to the ability of these compounds to inhibit phospholipase A2 and/or phospholipase C.
Gilfillan
A M
AM
Department of Pharmacology, Hoffmann-La Roche, Nutley, NJ 07110.
Wiggan
G A
GA
Hope
W C
WC
Patel
B J
BJ
Welton
A F
AF
D000818:Animals; D001381:Azepines / Q000494:pharmacology; D004224:Diterpenes; D046934:Ginkgolides; D005995:Glyceryl Ethers / Q000494:pharmacology*; D006636:Histamine Release / Q000187:drug effects; D006801:Humans; D007073:Immunoglobulin E / Q000276:immunology*; D007295:Inositol Phosphates / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D007783:Lactones / Q000494:pharmacology; D010741:Phospholipases A / Q000378:metabolism; D054467:Phospholipases A2; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D051381:Rats; D013373:Substance P / Q000378:metabolism; D013582:Synovial Fluid / Q000201:enzymology; D013844:Thiazoles / Q000494:pharmacology*; D014227:Triazines / Q000494:pharmacology; D014230:Triazoles; D014407:Tumor Cells, Cultured
D001381:Azepines; D004224:Diterpenes; D046934:Ginkgolides; D005995:Glyceryl Ethers; D007295:Inositol Phosphates; D007783:Lactones; D010972:Platelet Activating Factor; D013844:Thiazoles; D014227:Triazines; D014230:Triazoles; C052518:WEB 2086; C053235:Ro 19-3704; C063812:Ro 19-1400; D013373:Substance P; D007073:Immunoglobulin E; C045856:ginkgolide B; D007770:L-Lactate Dehydrogenase; D010741:Phospholipases A; D054467:Phospholipases A2