The mechanism of action of lymphokines. VII. Modulation of the action of macrophage migration inhibitory factor by antioxidants and drugs affecting thromboxane synthesis

Abstract

Guinea pig peritoneal exudate macrophages are active producers of oxygen radicals in response to membrane stimulation. We examined the involvement of oxygen radicals in the inhibition of macrophage migration caused by the lymphokine, macrophage migration inhibitory factor (MIF). It was found that the presence of scavengers of superoxide and hydrogen peroxide did not influence MIF action. Exogenous horseradish peroxidase, however, significantly enhanced the migration inhibitory effect of MIF. Among six scavengers of hydroxyl radicals and singlet oxygen that were tested, L-methionine (20-80 mM) and L-histidine (40-80 mM) were capable of preventing MIF action. Macrophage responsiveness to MIF was also blocked by the lipid antioxidant propyl gallate (0.125-0.25 mM). Lymphokine-induced inhibition of migration could not be prevented by inhibitors of phospholipase A2, cyclooxygenase, or lipoxygenase. The inhibiting of thromboxane synthetase, however, by imidazole, 1-benzylimidazole and the prostaglandin endoperoxide analogs U-51605 and U-44069 effectively prevented MIF action. These findings are compatible with the hypothesis that the inhibiton of macrophage migration by MIF is the result of reversible autotoxic damage by a yet unidentified product of the oxidative burst, possibly hypochlorous acid. Thromboxane also appears to be involved in MIF action probably by its adhesiveness increasing and proaggregatory actions. The intracellular target of the autotoxic attack and the relative importance of oxygen-derived products and thromboxane in the mediation of MIF-induced migration inhibition are unknown.