Role of ADAM17 in the ectodomain shedding of TNF-α and its receptors by neutrophils and macrophages

TNF‐α and its receptors TNFRI and TNFRII are cleaved from the surface of leukocytes by a proteolytic process referred to as ectodomain shedding. The role of a disintegrin and metalloproteinase 17 (ADAM17) in this process by the major professional phagocytes neutrophils and macrophages, the primary p...

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Bibliographic Details
Published in:	Journal of leukocyte biology Vol. 82; no. 1; pp. 173 - 176
Main Authors:	Bell, Jessica H., Herrera, Amy H., Li, Ying, Walcheck, Bruce
Format:	Journal Article
Language:	English
Published:	United States Society for Leukocyte Biology 01-07-2007
Subjects:	ADAM Proteins - metabolism ADAM Proteins - physiology ADAM17 Protein Animals Chimera Inflammation Leukocytes - metabolism Macrophages - enzymology Macrophages - physiology metalloprotease Mice Neutrophils - enzymology Neutrophils - physiology Peptide Hydrolases - metabolism Receptors, Tumor Necrosis Factor, Type I - metabolism Receptors, Tumor Necrosis Factor, Type II - metabolism Solubility Tumor Necrosis Factor-alpha - blood Tumor Necrosis Factor-alpha - metabolism
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Summary:	TNF‐α and its receptors TNFRI and TNFRII are cleaved from the surface of leukocytes by a proteolytic process referred to as ectodomain shedding. The role of a disintegrin and metalloproteinase 17 (ADAM17) in this process by the major professional phagocytes neutrophils and macrophages, the primary producers of TNF‐α during inflammation induction, is based entirely on indirect evidence, and other sheddases have been implicated as well. As Adam17 gene‐targeting in mice is lethal, we assessed the protease’s relative contribution to TNF‐α, TNFRI, and TNFRII shedding using radiation chimeric mice with leukocytes lacking functional ADAM17. We report ablated, soluble TNF‐α, TNFRI, and TNFRII production by neutrophils and macrophages stimulated with various microbial antigens and greatly reduced TNF‐α levels in vivo following inflammation induction. This is the first simultaneous analysis of TNF‐α, TNFRI, and TNFRII shedding by neutrophils and macrophages and the first direct evidence that ADAM17 is a primary and nonredundant sheddase.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	0741-5400 1938-3673
DOI:	10.1189/jlb.0307193