TY - JOUR
T1 - Role of ADAM17 in the ectodomain shedding of TNF-α and its receptors by neutrophils and macrophages
AU - Bell, Jessica H.
AU - Herrera, Amy H.
AU - Li, Ying
AU - Walcheck, Bruce
PY - 2007/7/1
Y1 - 2007/7/1
N2 - 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.
AB - 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.
KW - Inflammation
KW - Metalloprotease
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UR - http://www.scopus.com/inward/citedby.url?scp=34347391898&partnerID=8YFLogxK
U2 - 10.1189/jlb.0307193
DO - 10.1189/jlb.0307193
M3 - Article
C2 - 17510296
AN - SCOPUS:34347391898
SN - 0741-5400
VL - 82
SP - 173
EP - 176
JO - Journal of Leukocyte Biology
JF - Journal of Leukocyte Biology
IS - 1
ER -