EFFECTS OF METABOLITES OF LEUKOTRIENE B-4 ON HUMAN NEUTROPHIL MIGRATION AND CYTOSOLIC CALCIUM LEVELS

Leukotriene B-4 (LTB(4)) is metabolized by beta-oxidation, omega-oxida tion and the 12-hydroxyeicosanoid dehydrogenase/Delta(10)-reductase pa thway. We have investigated the effects of metabolites formed by the l atter pathway on calcium mobilization and migration in human neutrophi ls and have compared their potencies with those of other LTB(4) deriva tives. 12-Oxo-LTB(4) and 10,11-dihydro-LTB(4) were 60 to 100 times les s potent than LTB(4) in stimulating neutrophils, whereas 10,11-dihydro -12-oxo-LTB(4) and 10,11-dihydro-12-epi-LTB(4) exhibited still lower p otencies. The 6-trans isomers of 12-oxo-LTB(4) and 10,11-dihydro-12oxo -LTB(4) were much less potent than the 6-cis compounds. The EC(50) val ues for biologically and chemically (6-cis) synthesized 12-oxo-LTB(4) were similar, indicating that the 6,7-double bond is retained in the c is configuration in the biologically formed compound. Methylation of L TB(4) markedly reduced its effect on cytosolic calcium levels, whereas addition of a 3-hydroxyl group had a much more modest effect. Modific ations of the omega end of the molecule also resulted in tower potenci es for calcium mobilization. Nearly all of the compounds tested desens itized neutrophils to LTB(4)-induced calcium mobilization, which sugge sts that their effects were mediated by receptors for the latter compo und. However, modifications in the carboxyl end of the molecule had sm aller effects on desensitization than on calcium mobilization, whereas the reverse was true for modifications in the omega end of the molecu le. This suggests that the structural requirements for agonist-induced desensitization to LTB(4) may differ to some extent from the requirem ents for calcium mobilization.