Cutting edge: TNF-alpha-converting enzyme (TACE/ADAM17) inactivation in mouse myeloid cells prevents lethality from endotoxin shock.
TNF-alpha, a potent proinflammatory cytokine, is synthesized as a membrane-anchored precursor and proteolytically released from cells. Soluble TNF is the primary mediator of pathologies such as rheumatoid arthritis, Crohn's disease, and endotoxin shock. The TNF-alpha converting enzyme (TACE), a disintegrin and metalloprotease 17 (ADAM17), has emerged as the best candidate TNF sheddase, but other proteinases can also release TNF. Because TACE-deficient mice die shortly after birth, we generated conditional TACE-deficient mice to address whether TACE is the relevant sheddase for TNF in adult mice. In this study, we report that TACE inactivation in myeloid cells or temporal inactivation at 6 wk offers strong protection from endotoxin shock lethality in mice by preventing increased TNF serum levels. These findings corroborate that TACE is the major endotoxin-stimulated TNF sheddase in mouse myeloid cells in vivo, thereby further validating TACE as a principal target for the treatment of TNF-dependent pathologies.
Horiuchi
Keisuke
K
Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, Department of Medicine, Weill Medical College of Cornell University, New York, NY 10021, USA.
Kimura
Tokuhiro
T
Miyamoto
Takeshi
T
Takaishi
Hironari
H
Okada
Yasunori
Y
Toyama
Yoshiaki
Y
Blobel
Carl P
CP
D051722:ADAM Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D000072198:ADAM17 Protein; D000818:Animals; D019204:GTP-Binding Proteins / Q000235:genetics; D019426:Integrases / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D022423:Myeloid Cells / Q000201:enzymology*; D064547:Myxovirus Resistance Proteins; D012772:Shock, Septic / Q000201:enzymology / Q000517:prevention & control*
D064547:Myxovirus Resistance Proteins; C045073:Cre recombinase; D019426:Integrases; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse; D019204:GTP-Binding Proteins