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

J Leukoc Biol. 2007 Jul;82(1):173-6. doi: 10.1189/jlb.0307193. Epub 2007 May 17.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • ADAM Proteins / metabolism*
  • ADAM Proteins / physiology
  • ADAM17 Protein
  • Animals
  • Chimera
  • Inflammation
  • Leukocytes / metabolism
  • Macrophages / enzymology
  • Macrophages / physiology*
  • 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*


  • Receptors, Tumor Necrosis Factor, Type I
  • Receptors, Tumor Necrosis Factor, Type II
  • Tumor Necrosis Factor-alpha
  • Peptide Hydrolases
  • ADAM Proteins
  • ADAM17 Protein
  • Adam17 protein, mouse