Borland, Gillian, Murphy, Gillian and Ager, Ann ![]() |
Abstract
Although the enzyme or enzymes mediating shedding of L-selectin have not yet been identified, this activity can be blocked by synthetic hydroxamic acid-based inhibitors of metalloproteinases such as Ro 31-9790. However, the endogenous matrix metalloproteinase inhibitor tissue inhibitor of metalloproteinases (TIMP)-1 does not block L-selectin shedding. Here, we report that TIMP-3, but not TIMP-2, inhibits L-selectin shedding from mouse and human lymphocytes, Jurkat T cells, and human monocytes. TIMP-3 has an IC50 of 0.3–0.4 μm on these cell types compared with 0.7–4.8 μm for Ro 31-9790. A metalloproteinase (tumor necrosis factor-α (TNF-α)-converting enzyme; ADAM17) has recently been identified which cleaves the pro-form of TNF-α to produce soluble cytokine. We compared inhibition of L-selectin shedding by TIMPs and Ro 31-9790 with inhibition of TNF-α shedding from human monocytes. TIMP-3 inhibited TNF-α shedding (IC50 of 0.1 μm), as did Ro 31-9790 (IC50 of 0.4 μm). TIMP-2 had a partial effect, and TIMP-1 did not inhibit. This study confirms that L-selectin sheddase is a metalloproteinase, but not a matrix metalloproteinase, and investigates the relationship between shedding of L-selectin and TNF-α.
Item Type: | Article |
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Date Type: | Publication |
Status: | Published |
Schools: | Medicine Systems Immunity Research Institute (SIURI) |
Subjects: | R Medicine > R Medicine (General) |
Publisher: | American Society for Biochemistry and Molecular Biology |
ISSN: | 0021-9258 |
Last Modified: | 20 Oct 2022 09:54 |
URI: | https://orca.cardiff.ac.uk/id/eprint/33478 |
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