Effect of inflammatory and antiinflammatory stimuli on acyloxyacyl hydrolase gene expression and enzymatic activity in murine macrophages

Abstract

Acyloxyacyl hydrolase (AOAH) is an enzyme found in macrophages and neutrophils that specifically cleaves the acyloxyacyl moieties of lipopolysaccharide (LPS), thus rendering it non-toxic for human cells. In the present study, we demonstrate that LPS augments AOAH mRNA expression (10-20-fold) in murine macrophages. Following LPS treatment (100 ng/m]), AOAH mRNA was induced by 2 h, peaked at 6 h, and was sustained over 72 h. Optimal induction of AOAH mRNA was observed with as little as 0.1 ng/ml LPS. LPS also induced a concomitant increase in AOAH enzymatic activity in cytosolic extracts from murine macrophages and the ability of macrophages to deacylate LPS was not diminished in endotoxin-tolerized macrophages. LPS-stimulated AOAH mRNA expression was cycloheximide sensitive, indicating that de novo protein synthesis is required for AOAH mRNA production. Moreover, AOAH mRNA expression was also induced by IFN-γ. LPS-stimulated mRNA expression was not suppressed by either dexamethasone or IL-10. Finally, intraperitoneal challenge of mice with 25 μg of LPS resulted in increases in AOAH mRNA in both the lung (∼3-fold) and in the liver (∼6-fold). A possible role for LPS-inducible AOAH in the elimination of LPS is discussed.

Overproduction of Acyloxyacyl Hydrolase by Macrophages and Dendritic Cells Prevents Prolonged Reactions to Bacterial Lipopolysaccharide In Vivo

“…1B). LPS thus induces a significant but transient increase in AOAH activity in wildtype mice, in agreement with previous findings [16]. The increase in AOAH activity roughly paralleled the time-course of hepatic LPS deacylation, which occurs gradually over 1 to 3 days [17].…”

“…Cody et al showed that LPS upregulates AOAH mRNA expression in vivo [16]. Here we found that a single low dose of LPS is able to augment hepatic AOAH activity by approximately sixfold, with increased levels for up to five days after challenge (Fig.…”

Polymorphisms in the novel gene acyloxyacyl hydroxylase (AOAH) are associated with asthma and associated phenotypes

“…Similarly, AOAH activity can be induced after LPS exposure in murine dendritic cells 59 and macrophages. 65 Perhaps only subjects with either or both of these variants would have increased tIgE concentrations. In the current study we examined 28 SNPs throughout the AOAH gene, including 4 SNPs within approximately 5 kb of each other in intron 12, flanking exon 13.…”

A Host Lipase Detoxifies Bacterial Lipopolysaccharides in the Liver and Spleen

“…It is thus possible that subsequent doses of LPS would be deacylated more rapidly than was the single bolus injection studied here. Indeed, Cody et al (54) also found that macrophage AOAH expression could be induced in vitro by tumor necrosis factor and interferon-␥, was not inhibited by interleukin-10 or dexamethasone, and occurred in endotoxin-tolerant cells. Increases in AOAH activity may thus play a role in reducing responses to recurring exposures to LPS or Gram-negative bacteria in vivo.…”