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Role of ADAM17 in the ectodomain shedding of TNF‐α and its receptors by neutrophils and macrophages
Author(s) -
Bell Jessica H.,
Herrera Amy H.,
Li Ying,
Walcheck Bruce
Publication year - 2007
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.0307193
Subject(s) - ectodomain , biology , tumor necrosis factor alpha , inflammation , granulocyte macrophage colony stimulating factor , receptor , immunology , microbiology and biotechnology , metalloproteinase , cytokine , matrix metalloproteinase , biochemistry
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.