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Cutting Edge: TNF--Converting Enzyme (TACE/ADAM17) Inactivation in Mouse Myeloid Cells Prevents Lethality from Endotoxin Shock¹

Keisuke Horiuchi^*,,, Tokuhiro Kimura, Takeshi Miyamoto^,¶, Hironari Takaishi, Yasunori Okada, Yoshiaki Toyama and Carl P. Blobel^2,*

^* Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, Department of Medicine and Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, NY 10021; Department of Orthopedic Surgery, Department of Anti-Aging Orthopedic Research, Department of Pathology, and ^¶ Department of Musculoskeletal Reconstruction and Regeneration Surgery, Keio University, School of Medicine, Tokyo, Japan

TNF-, 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- 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant R01GM64750 (to C.P.B.) and the Nagao Memorial Fund, the Nakatomi Foundation, and Grants-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (19591765) (to K.H.).

² Address correspondence and reprint requests to Dr. Carl P. Blobel, Arthritis and Tissue Degeneration Program, Caspary Research Building, Room 426, Hospital for Special Surgery, 535 East 70th Street, New York, NY, 10021. E-mail address: blobelc{at}hss.edu

³ Abbreviations used in this paper: TACE, TNF--converting enzyme; ADAM, a disintegrin and metalloprotease; mEF, mouse embryonic fibroblast; pIpC, polyinosinic-polycytidylic acid.

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