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.