Preexposure of mouse peritoneal macrophages to lipopolysaccharide and other stimuli enhances the nitric oxide response to secondary stimuli

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Abstract
The aim of this study was to compare the regulation of the production of tumor necrosis factor-α (TNF-α) and secondary nitric oxide (NO) in macrophages submitted to a sequence of two stimulations. Pre-exposure for 18h of mouse thioglycollate-elicited peritoneal macrophages to low doses (1–10 ng/ml) of lipopolysaccharide (LPS), in the presence or absence of serum, induces on one hand a desensitization (endotoxin tolerance) for secondary TNF-α reponses to LPS and, on the other hand, a 4 fold increase (priming) of serondary NO responses. Preexposure to components from Gram-positive bacteria (lipoteichoic acid, peptidoglycan) and to a synthetic lipid structurally related to lipid A (compound M4), induced similar effects. In contrast to the desensitization for TNF-α secretion, the priming for NO production was not mimicked by sodium nitroprusside, a generator of NO. The results suggest that concomitant but distinct activation pathways induced by LPS and other agents can be dissociated by serum-independent modulation processes elicited by preexposure of the cells to LPS itself, or to other stimuli.