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 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 alpha (TNF-alpha) 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.
Le-Barillec
K
K
Unité Associée IP/INSERM 485, Institut Pasteur, Paris, France.
Pidard
D
D
Balloy
V
V
Chignard
M
M
D056649:Cathepsin G; D002403:Cathepsins / Q000502:physiology*; D015536:Down-Regulation; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008262:Macrophage Activation; D008264:Macrophages / Q000502:physiology*; D009000:Monocytes / Q000502:physiology*; D009504:Neutrophils / Q000378:metabolism*; D012697:Serine Endopeptidases
D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D002403:Cathepsins; D012697:Serine Endopeptidases; C534094:CTSG protein, human; D056649:Cathepsin G