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Published online before print May 17, 2007

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(Journal of Leukocyte Biology. 2007;82:173-176.)
© 2007 by Society for Leukocyte Biology

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

Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, Minnesota, USA

¹ Correspondence: University of Minnesota, 295j AS/VM Bldg., 1988 Fitch Avenue, St. Paul, MN 55108, USA. E-mail: walch003{at}umn.edu

ABSTRACT

TNF- 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- 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-, TNFRI, and TNFRII shedding using radiation chimeric mice with leukocytes lacking functional ADAM17. We report ablated, soluble TNF-, TNFRI, and TNFRII production by neutrophils and macrophages stimulated with various microbial antigens and greatly reduced TNF- levels in vivo following inflammation induction. This is the first simultaneous analysis of TNF-, TNFRI, and TNFRII shedding by neutrophils and macrophages and the first direct evidence that ADAM17 is a primary and nonredundant sheddase.

Key Words: inflammation • metalloprotease

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