PMID- 19767822 OWN - NLM STAT- MEDLINE DCOM- 20091127 LR - 20161125 IS - 1208-6002 (Electronic) IS - 0829-8211 (Linking) VI - 87 IP - 4 DP - 2009 Aug TI - Involvement of a disintegrin and metalloproteinase 10 and 17 in shedding of tumor necrosis factor-alpha. PG - 581-93 LID - 10.1139/o09-015 [doi] AB - Tumor necrosis factor-alpha (TNF-alpha) 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-alpha, it is not known whether ADAM17 is solely responsible for that process in any type of cells. To identify the TNF-alpha 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-alpha. We then performed RNA interference experiments and confirmed that ADAM10 and ADAM17 were in fact involved in TNF-alpha 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 UVfemale2, ADAM10 and ADAM17 were equally involved in TNF-alpha 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-alpha sheddase and that their significance could be determined by their expression levels and the abundance of tissue inhibitor of metalloproteinases. FAU - Hikita, Atsuhiko AU - Hikita A AD - Department of Pathomechanisms, Clinical Research Center, National Hospital Organization Sagamihara Hospital, Sagamihara, Kanagawa 228-8522, Japan. FAU - Tanaka, Nobuho AU - Tanaka N FAU - Yamane, Shoji AU - Yamane S FAU - Ikeda, Yasuko AU - Ikeda Y FAU - Furukawa, Hiroshi AU - Furukawa H FAU - Tohma, Shigeto AU - Tohma S FAU - Suzuki, Ryuji AU - Suzuki R FAU - Tanaka, Sakae AU - Tanaka S FAU - Mitomi, Hiroyuki AU - Mitomi H FAU - Fukui, Naoshi AU - Fukui N LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - Canada TA - Biochem Cell Biol JT - Biochemistry and cell biology = Biochimie et biologie cellulaire JID - 8606068 RN - 0 (DNA Primers) RN - 0 (Membrane Proteins) RN - 0 (Tumor Necrosis Factor-alpha) RN - EC 3.4.- (Amyloid Precursor Protein Secretases) RN - EC 3.4.24.- (ADAM Proteins) RN - EC 3.4.24.81 (ADAM10 Protein) RN - EC 3.4.24.81 (Adam10 protein, mouse) RN - EC 3.4.24.86 (ADAM17 Protein) RN - EC 3.4.24.86 (ADAM17 protein, human) RN - EC 3.4.24.86 (Adam17 protein, mouse) SB - IM MH - ADAM Proteins/*physiology MH - ADAM10 Protein MH - ADAM17 Protein MH - Amyloid Precursor Protein Secretases/*physiology MH - Animals MH - Base Sequence MH - Cell Line MH - DNA Primers MH - Enzyme-Linked Immunosorbent Assay MH - Humans MH - Macrophages/metabolism MH - Membrane Proteins/*physiology MH - Mice MH - NIH 3T3 Cells MH - Reverse Transcriptase Polymerase Chain Reaction MH - Tumor Necrosis Factor-alpha/*metabolism EDAT- 2009/09/22 06:00 MHDA- 2009/12/16 06:00 CRDT- 2009/09/22 06:00 PHST- 2009/09/22 06:00 [entrez] PHST- 2009/09/22 06:00 [pubmed] PHST- 2009/12/16 06:00 [medline] AID - o09-015 [pii] AID - 10.1139/o09-015 [doi] PST - ppublish SO - Biochem Cell Biol. 2009 Aug;87(4):581-93. doi: 10.1139/o09-015.