Role of ADAM17 in the ectodomain shedding of TNF-alpha and its receptors by neutrophils and macrophages.
TNF-alpha 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-alpha 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-alpha, TNFRI, and TNFRII shedding using radiation chimeric mice with leukocytes lacking functional ADAM17. We report ablated, soluble TNF-alpha, TNFRI, and TNFRII production by neutrophils and macrophages stimulated with various microbial antigens and greatly reduced TNF-alpha levels in vivo following inflammation induction. This is the first simultaneous analysis of TNF-alpha, TNFRI, and TNFRII shedding by neutrophils and macrophages and the first direct evidence that ADAM17 is a primary and nonredundant sheddase.
Bell
Jessica H
JH
Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, Minnesota 55108, USA.
Herrera
Amy H
AH
Li
Ying
Y
Walcheck
Bruce
B
D051722:ADAM Proteins / Q000378:metabolism* / Q000502:physiology; D000072198:ADAM17 Protein; D000818:Animals; D002678:Chimera; D007249:Inflammation; D007962:Leukocytes / Q000378:metabolism; D008264:Macrophages / Q000201:enzymology / Q000502:physiology*; D051379:Mice; D009504:Neutrophils / Q000201:enzymology / Q000502:physiology*; D010447:Peptide Hydrolases / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism*; D012995:Solubility; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000378:metabolism*
D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D010447:Peptide Hydrolases; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse