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33. Involvement of a disintegrin and metalloproteinase 10 and 17 in shedding of tumor necrosis factor-α

Author

Hikita, Atsuhiko, Tanaka, Nobuho, Yamane, Shoji, Ikeda, Yasuko, Furukawa, Hiroshi, Tohma, Shigeto, Suzuki, Ryuji, Tanaka, Sakae, Mitomi, Hiroyuki, and Fukui, Naoshi

Subjects
Proteolysis -- Research, Molecular biology -- Research, Metalloproteins -- Chemical properties, Tumor necrosis factor -- Health aspects -- Natural history -- Chemical properties, Biological sciences, Chemical properties, Research, Natural history, Health aspects
Abstract

Tumor necrosis factor-a (TNF-α) is initially synthesized as a membrane-bound protein and converted into a soluble form by proteolytic cleavage. Although a disintegrin and metalloproteinase 17 (ADAM17) is considered to be the primary sheddase for TNF-α, it is not known whether ADAM17 is solely responsible for that process in any type of cells. To identify the TNF-α sheddase(s) in varieties of cells, we performed experiments using a unique screening system and observed that ADAM9, ADAM10, ADAM17, and ADAM19 were capable of cleaving TNF-α. We then performed RNA interference experiments and confirmed that ADAM10 and ADAM17 were in fact involved in TNF-α shedding in 293A cells. In mouse macrophages, ADAM17 was confirmed to be the primary sheddase, but the involvement of ADAM10 was also demonstrated. In NIH3T3 cells, ADAM10 could be more important in the shedding than ADAM17. In mouse vascular endothelial cell line UVY2, ADAM10 and ADAM17 were equally involved in TNF-α shedding, whereas ADAM17 was a major sheddase in human osteoarthritic chondrocytes. From these observations and others, we concluded that both ADAM10 and ADAM17 can be a TNF-α sheddase and that their significance could be determined by their expression levels and the abundance of tissue inhibitor of metalloproteinases. Key words: TNF-α, ADAM10, ADAM17, TIMP, ectodomain shedding. Resume : Le TNF-α est d'abord synthetise sous forme de proteine liee a la membrane et sa forme soluble est produite par un clivage proteolytique. Meme si la desintegrine metalloprotease ADAM17 est consideree comme la principale sheddase agissant sur le TNF-α, on ignore si ADAM17 est la seule responsable de ce processus pour tous les types de cellules. Afin d'identifier les sheddases de TNF-α dans une variete de cellules, nous avons realise des experiences a l'aide d'un systeme de criblage unique et nous avons observe que ADAM9, ADAM10, ADAM17 et ADAM19 sont capables de cliver le TNF-α. Nous avons ensuite realise des experiences d'interference par ARN et nous avons confirme que ADAM10 et ADAM17 sont effectivement impliquees dans la liberation du TNF-α chez les cellules 293A. Chez les macrophages de souris, ADAM17 s'est averee comme sheddase principale mais l'implication de ADAM10 a aussi ete demontree. Chez les cellules NIH3T3, ADAM10 pourrait etre plus importante pour la liberation que ADAM17. Dans la lignee cellulaire vasculaire endotheliale UVY2, ADAM10 et ADAM17 sont egalement impliquees dans la liberation de TNF-α, alors que ADAM17 est la principale sheddase chez les chondrocytes osteoarthritiques humains. A partir de ces observations et d'autres, nous avons conclu que ADAM10 et ADAM17 peuvent toutes deux etre des sheddases du TNF-α et que leur importance pourrait etre determinee par leur niveau d'expression et par l'abondance des TIMP ('tissue inhibitor of metalloproteinases'). Mots-cles: TNF-α, ADAM10, ADAM17, TIMP, liberation d'ectodomaine. [Traduit par la Redaction], Introduction Ectodomain shedding is a process in which transmembrane proteins are proteolytically released from the plasma membrane. Ectodomain shedding modifies the biologic and pathologic functions of the substrate protein. For [...]

Published
2009

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