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

Jessica H. Bell, Amy H. Herrera, Ying Li, Bruce Walcheck

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135 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)173-176
Number of pages4
JournalJournal of Leukocyte Biology
Issue number1
StatePublished - Jul 1 2007


  • Inflammation
  • Metalloprotease


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