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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 alpha 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.