ALTERED RESPONSES TO MODULATORS OF GUANINE-NUCLEOTIDE BINDING-PROTEIN ACTIVITY IN ENDOTOXIN TOLERANCE

The effects of cholera toxin or pertussis toxin and nonhydrolyzable GTP analogs on Salmonella enteritidis endotoxin stimulation of iTxB2 and i6-keto-PGF1α synthesis in control and endotoxin tolerant rat pertioneal macrophages were determined. Pretreatment with pertussis toxin alone had no effect on basal macrophage iTxB2 or i6-keto-PGF1α production, but pertussis toxin (0.1, 1.0 and 10 ng/ml) significantly inhibited endotoxin-stimulated iTxB2 and i6-keto-PGF1α synthesis. Pretreatment with cholera toxin, which did not affect basal iTxB2 or i6-keto-PGF1α synthesis, significantly enhanced endotoxin-induced synthesis of iTxB2 and i6-keto-PGF1α. The effects of pertussis and cholera toxin with or without endotoxin were significantly (P < 0.05) less in macrophages from endotoxin tolerant rats compared to control macrophages. GTP[γ-S] (100 μM) significantly increased iTxB2 synthesis and significantly augmented endotoxin-stimulated iTxB2 synthesis in control macrophages (P < 0.05). However, in macrophages from endotoxin tolerant rats the effect of GTP[γ-S] on iTxB2 synthesis was significantly less (P < 0.05) compared to control macrophages. Collectively, these data suggest that: (1) guanine nucleotide binding regulatory proteins mediate endotoxin-stimulated arachidonic acid metabolism in rat peritoneal macophages; and (2) endotoxin tolerance induces alterations in guanine nucleotide binding protein activity. © 1990.