Enzymatically deacylated lipopolysaccharide (LPS) can antagonize LPS at multiple sites in the LPS recognition pathway.

The Journal of Biological Chemistry
Richard L Kitchens, Robert Munford

Abstract

Like other tetraacyl partial structures of lipopolysaccharide (LPS) and lipid A, LPS that has been partially deacylated by acyloxyacyl hydrolase can inhibit LPS-induced responses in human cells. To identify the site(s) of inhibition in the LPS recognition pathway, we analyzed the apparent binding affinities and interactions of 3H-labeled enzymatically deacylated LPS (dLPS) and [3H]LPS with CD14, the LPS receptor, on THP-1 cells. Using (i) incubation conditions that prevented ligand internalization and (ii) defined concentrations of LPS binding protein (LBP), which facilitates LPS and dLPS binding to CD14, we found that dLPS can antagonize LPS in at least three ways. 1) When the concentration of LBP in the medium was suboptimal for promoting LPS-CD14 binding, low concentrations of dLPS were able to compete with LPS for binding CD14, suggesting competition between LPS and dLPS for engaging LBP. 2) When LBP was present in excess, dLPS could compete with LPS for binding CD14, but only at dLPS concentrations that were at or above its KD for binding CD14 (100 ng/ml). 3) In contrast, substoichiometric concentrations of dLPS (1 ng/ml) inhibited LPS-induced (3 ng/ml) interleukin-8 release without blocking LPS binding to CD14. Functional...Continue Reading

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