Lead inhibits intracellular killing of Leishmania parasites and extracellular cytolysis of target cells by macrophages exposed to macrophage activating factor.
Activation of Leishmania enriettii-infected mouse macrophages in vitro by treatment with macrophage activating factor (MAF)-rich media supplemented with lipopolysaccharide (LPS) leads to rapid killing of the microorganism. When exposed to MAF + LPS in the presence of 30-100 microM lead acetate, however, macrophages failed to destroy the parasites. This effect was not due to lead toxicity for macrophages. Decreased microbicidal activity correlated with depressed respiratory burst as determined by measurements of glucose oxidation through the hexose monophosphate shunt (HMPS). Lead had little effect on intracellular parasite killing induced by exposure of macrophages to the electron carrier methylene blue; HMPS in such cells was similarly little affected, indicating that chemical triggering of this pathway bypassed the lead-imposed blockade. Lead also abolished macrophage activation measured by the lysis of tumor target cells in vitro. The metal failed, however, to interfere with target-cell lysis by macrophages activated in lead-free medium, suggesting that lead inhibited the acquisition of the activated state rather than the functional expression of such state. Lead did not prevent the binding of radiolabelled interferon-gamma to macrophages; it did, however, slow down receptor turnover and degradation of bound interferon. Lead also inhibited the LPS-triggered cytotoxicity in macrophages previously exposed to interferon-gamma in lead-free medium, suggesting that depressed intracellular killing might result from an effect on both the priming (interferon or MAF-dependent) and the triggering (LPS-dependent) steps of activation.
Mauël
J
J
Institute of Biochemistry, University of Lausanne, Epalinges, Switzerland.
Ransijn
A
A
Buchmüller-Rouiller
Y
Y
D000818:Animals; D005260:Female; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000378:metabolism; D007854:Lead / Q000493:pharmacokinetics / Q000494:pharmacology*; D007894:Leishmania mexicana; D008222:Lymphokines / Q000037:antagonists & inhibitors*; D008262:Macrophage Activation / Q000187:drug effects*; D016215:Macrophage-Activating Factors; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008751:Methylene Blue / Q000494:pharmacology; D051379:Mice; D010427:Pentose Phosphate Pathway / Q000187:drug effects; D011994:Recombinant Proteins
D008222:Lymphokines; D016215:Macrophage-Activating Factors; D011994:Recombinant Proteins; D007854:Lead; D007371:Interferon-gamma; D008751:Methylene Blue