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.