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CD30 Shedding from Karpas 299 Lymphoma Cells Is Mediated by TNF--Converting Enzyme¹

Hinrich P. Hansen^2,*, Sebastian Dietrich^*, Tatiana Kisseleva^3,*, Thilo Mokros^*, Rolf Mentlein, Hans H. Lange^*, Gillian Murphy and Hilmar Lemke^*

Departments of ^* Biochemistry and Anatomy, University of Kiel, Kiel, Germany; and School of Biological Science, University of East Anglia, Norwich, United Kingdom

CD30 is a costimulatory receptor on activated lymphocytes and a number of human lymphoma cells. Specific ligation of membrane-bound CD30 or cellular stimulation by PMA results in a metalloproteinase-mediated down-regulation of CD30 and release of its soluble ectodomain (sCD30). In this report, it is demonstrated that PMA-induced CD30 cleavage from Karpas 299 cells was mediated by a membrane-anchored metalloproteinase which was active on intact cells following 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate extraction of membrane preparations. Moreover, CD30 shedding was blocked by the synthetic hydroxamic acid-based metalloproteinase inhibitor BB-2116 (IC₅₀, 230 nM) and the natural tissue inhibitor of metalloproteinases (TIMP)-3 (IC₅₀, 30 nM), but not by the matrix metalloproteinase inhibitors TIMP-1 and TIMP-2. This inhibition profile is similar to that of the TNF-- converting enzyme (TACE) and, indeed, mRNA transcripts of the membrane-bound metalloproteinase-disintegrin TACE could be detected in Karpas 299 cells. The ectodomain of TACE was expressed in bacteria as a GST fusion protein (GST-TACE) which cleaved CD30 from the surface of Karpas 299 cells and concomitantly increased the level of sCD30 in the cell supernatants. Hence, TACE does not only control the release of TNF-, but also that of sCD30.

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