Differential alteration of lipoxygenase and cyclooxygenase metabolism by rat peritoneal macrophages induced by endotoxin tolerance

Altered macrophage arachidonic acid metabolism may play a role in endotoxic shock and the phenomenon of endotoxin tolerance induced by repeated injections of endotoxin. Studies were initiated to characterize both lipoxygenase metabolite formation by endotoxin tolerant and non-tolerant macrophages in response to 4 different stimuli, i.e. endotoxin, glucan, zymosan, and the calcium ionophore A23187. In contrast to previous reports of decreased prostaglandin synthesis by tolerant macrophages, A23187-stimulated immunoreactive (i) leukotriene (LT)C₄/D₄ and prostaglandin (PG)E₂ production by tolerant cells was greater than that by non-tolerant controls (p<0.001). However, A23187-stimulated i-6-keto-PGF_1α levels were lower in tolerant macrophages compared to controls. Stimulation of prostaglandin and thromboxane (Tx)B₂ synthesis by endotoxin or glucam was significantly less in tolerant macrophages compaared to controls (p<0.05). iLTC₄/D₄ production was not significantly stimulated by endotoxin or glucan, but was stimulated by zymosan in the non-tolerant cells. Synthesis ofb iLTB₄ by control macrophages was stimulated by endotoxin (p<0.01). These results demonstrate that arachidonic acid metabolism via the lipoxygenase and cyclooxygenase pathways in macrophages is differentially altered by endotoxin tolerance.