A major property of monocytes/macrophages is to recognize and to be activated by bacterial wall components such as LPS, through membrane receptors including the key element CD14. We demonstrate that CD14 expression is down-regulated, as judged by flow cytometry analysis, upon incubation of human monocytes with purified cathepsin G (CG), a releasable neutrophil serine proteinase. The progressive decrease of CD14 expression due to increasing concentrations of CG highly correlates (P < 0.0001) with the decreased synthesis of tumor necrosis factor α (TNF-α) in response to lipopolysaccharide (LPS). This effect is dependent on the enzymatic activity of CG but is not exerted through an activation of monocytes. Immunoblot analysis reveals that CD14 (M_r = 57,000) is directly cleaved by CG and released into the extracellular medium as a high-M_r species (M_r = 54,000). In this context, incubation of monocytes with activated neutrophils leads to a down-regulation of CD14 expression, a process blocked by a serine proteinase inhibitor. These data suggest a paradoxical anti-inflammatory property for CG.