Desensitization of Macrophages to Endotoxin Effects Is Not Correlated with a Down-Regulation of Lipopolysaccharide-Binding Sites

Bacterial endotoxin (LPS) can induce a tolerance to its own effects in vitro, in macrophages. To achieve a better understanding of the mechanism of this type of desensitization, we studied the regulation of the production of interleukin 1, interleukin 6, and tumor necrosis factor α by mouse peritoneal macrophages in response to LPS, after a preliminary exposure to LPS or to structurally related synthetic lipids. The concomitant down-regulation of LPS-binding sites was also analyzed. Complete desensitization of macrophages by LPS treatment was accompanied by a decrease of up to 70% in the number of LPS-binding sites. Preexposure of the cells to synthetic lipids also could induce down-regulation of LPS-binding sites and desensitization for cytokine production. However, there was no correlation between the structures that induce desensitization and those that elicit a down-regulation of LPS receptors. Furthermore, some synthetic compounds induced in the cells a restricted state of tolerance, characterized by a lack of secretion of only one cytokine in response to LPS. The results show that down-regulation of LPS receptors is not a prerequisite for the induction of LPS tolerance, and that different LPS substructures can down-regulate differently the various responses of the cells to LPS, thus suggesting that different pathways are operative for induction of endotoxin tolerance.