Human neutrophil cathepsin G down-regulates LPS-mediated monocyte activation through CD14 proteolysis

A major property of monocytes/macrophages is to recognize and to be activat ed by bacterial wall components such as LPS, through membrane receptors inc luding the key element CD14. We demonstrate that CD14 expression is down-re gulated, as judged by flow cytometry analysis, upon incubation of human mon ocytes with purified cathepsin G (CG), a releasable neutrophil serine prote inase. The progressive decrease of CD14 expression due to increasing concen trations of CG highly correlates (P < 0.0001) with the decreased synthesis of tumor necrosis factor alpha (TNF-alpha) in response to lipopolysaccharid e (LPS), This effect is dependent on the enzymatic activity of CG but is no t exerted through an activation of monocytes. Immunoblot analysis reveals t hat CD14 (M-r = 57,000) is directly cleaved by CG and released into the ext racellular medium as a high-M-r species (M-r = 54,000). In this context, in cubation of monocytes with activated neutrophils leads to a down-regulation of CD14 expression, a process blocked by a serine proteinase inhibitor. Th ese data suggest a paradoxical anti-inflammatory property for CG.