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Tissue inhibitor of metalloproteinases-3 inhibits shedding of L-selectin from leukocytes

Borland, Gillian, Murphy, Gillian and Ager, Ann 1999. Tissue inhibitor of metalloproteinases-3 inhibits shedding of L-selectin from leukocytes. Journal of Biological Chemistry 274 (5) , pp. 2810-2815. 10.1074/jbc.274.5.2810

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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
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: 04 Jun 2017 04:08
URI: http://orca-mwe.cf.ac.uk/id/eprint/33478

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