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

Abstract

The aim of this study was to compare the regulation of the production of tumor necrosis factor-alpha (TNF-alpha) and secondary nitric oxide (NO) in macrophages submitted to a sequence of two stimulations. Pre-exposure for 18 h 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-alpha responses to LPS and, on the other hand, a 4 fold increase (priming) of secondary 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-alpha 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 pre-exposure of the cells to LPS itself, or to other stimuli.

Synergy and Cross-Tolerance Between Toll-Like Receptor (TLR) 2- and TLR4-Mediated Signaling Pathways

“…Several previous studies reported that production of NO and IL-10 was induced by LPS even in the LPStolerant cells (19,20). These data seem contradictory to our findings; however, in these papers macrophages were pretreated with a low concentration of LPS (Ͻ20 ng/ml).…”

“…An adaptor molecule, MyD88, is involved in the signaling pathway via TLR4 (19,20). Upon stimulation, MyD88, which binds to TLR4, recruits IRAK to the receptor.…”

“…Several reports indicated that the induction of NO and IL-10 was not affected in LPS tolerance (1,19,20). We analyzed mRNA expression of inducible NO synthase (iNOS) and IL-10 by RT-PCR (Fig.…”

IL-12 Suppression During Experimental Endotoxin Tolerance: Dendritic Cell Loss and Macrophage Hyporesponsiveness

“…Controversy surrounds the issue of NO regulation in LPS-tolerized cells (25,(35)(36)(37)(38). In our hands, NO production by BALB/c splenocytes and peritoneal macrophages was inhibited after either in vivo or in vitro sensitization with LPS (data not shown), indicating that NO synthase activity is suppressed during LPS tolerance and arguing against a role for NO in IL-12 inhibition in this model.…”

Role of IFN-γ on dissociation between nitric oxide and TNF/IL-6 production by murine peritoneal cells after restimulation with bacterial lipopolysaccharide

“…This phenomenon is observed not only in macrophages and non-macrophage cells in vitro [12], but also in animal models as well [13]. It has also been reported that pretreatment with LPS primes macrophages for enhanced NO production to a second stimulation with LPS [14][15][16][17]. The mechanisms of the NO production in LPSstimulated macrophages and its regulation in interaction with other cells have not been clarified.…”