MULTIPLE PATHWAYS FOR SIGNAL TRANSDUCTION IN THE REGULATION OF ARACHIDONIC-ACID METABOLISM IN RAT PERITONEAL-MACROPHAGES

The roles of guanine nucleotide-binding proteins (G-proteins) and cyclic AMP (cAMP) in signal-transduction of inflammatory stimuli leading to arachidonic acid metabolism in resident rat peritoneal macrophages (RPM) were investigated. Opsonized zymosan, targeting multiple receptors and latex particles coated with IgG (latex-IgG), targeting Fc receptors, were used as models of in vivo inflammatory stimuli encountered by macrophages. A comparison of the patterns of eicosanoid products produced in response to these stimuli showed differences: opsonized zymosan stimulated production of more leukotriene B4 (LTB4) than prostaglandin E2 (PGE2), while latex-IgG stimulated production of more PGE2 than LTB4. Non-selective stimulation of G-proteins by GTP and non-hydrolyzable analogs of GTP also stimulated arachidonic acid metabolism; these agents were not selective for PGE2 or LTB4 production. Cholera toxin, however, selectively stimulated production of PGE2 rather than LTB4 and also increased intracellular cAMP concentrations. The increased cAMP did not appear to mediate cholera toxin stimulation since forskolin, which also increased cAMP, was inhibitory to PGE2 production. This suggests that latex-IgG and cholera toxin may activate arachidonic acid metabolism through a G-protein other than Gs to induce PGE2 production specifically. The effects of pertussis toxin were biphasic: a partial inhibitory effect was observed at a low concentration of pertussis toxin (1 ng/ml) on opsonized zymosan or latrix-IgG stimulated arachidonic acid metabolism, while a high concentration of pertussis toxin (100 ng/ml) augmented the stimuli. A pertussis toxin-sensitive G-protein, possibly Gi, may therefore mediate a portion of the stimulatory signals. We have concluded that multiple pathways probably exist for opsonized zymosan and latex-IgG stimulation of arachidonic acid metabolism potentially involving multiple G-proteins. © 1990.