Lipopolysaccharide Pretreatment Produces Macrophage Endotoxin Tolerance via a Serum-Independent Pathway

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Lipopolysaccharide activation (LPS2a) of macrophages is thought to occur via a CD14-dependent mechanism with a requirement for the serum factor, lipopolysaccharide binding protein. LPS-stimulated, CD14-dependent signal transduction is associated with phosphorylation of mitogen-activated protein kinase (MAPK), nuclear factor-kappa B (NF-kappa B) translocation, and secretion of tumor necrosis factor (TNF) and interleukin-1 (IL-1). Macrophage endotoxin tolerance after low-dose LPS pretreatment (LPSp) is characterized by inhibition of LPSa-stimulated TNF and augmentation of IL-1 secretion. We sought to determine the role of CD14-dependent pathways in the induction of endotoxin tolerance by comparing the effects of LPS (p) in the presence or absence of serum.


Murine peritoneal macrophages were exposed to a range of LPSp concentrations in the presence or absence of serum. MAPK activation and NF-kappa B were assayed 30 minutes after LPSp stimulation. TNF production and IL-1 were measured 6 hours after stimulation with 100 ng/mL LPSa, with or without 24-hour 10 ng/mL LPSp.


In the presence of serum, 100 ng/mL LPSp activated MAPK and NF-kappa B, whereas no activation of MAPK or NF-kappa B was seen at this LPSp concentration in the absence of serum. The absence of serum during 10 ng/mL LPSp did not prevent LPSp-mediated inhibition of TNF secretion, and it significantly augmented IL-1 secretion after stimulation with 100 ng/mL LPSa in the presence of serum.


Induction of the alterations in subsequent LPSa-stimulated cytokine secretion characteristic of endotoxin tolerance by LPSp occurs via a serum-independent signal transduction pathway.

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