Cytokine stimulated vascular cell adhesion molecule-1 (VCAM-1) ectodomain release is regulated by TIMP-3

Singh, Robert J.R., Mason, Justin C., Lidington, Elaine A., Edwards, Dylan R., Nuttall, Robert K., Khokha, Rama, Knauper, Vera ORCID: https://orcid.org/0000-0002-3965-9924, Murphy, Gillian and Gavrilovic, Jelena 2005. Cytokine stimulated vascular cell adhesion molecule-1 (VCAM-1) ectodomain release is regulated by TIMP-3. Cardiovascular Research 67 (1) , pp. 39-49. 10.1016/j.cardiores.2005.02.020

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Abstract

Objectives: Vascular cell adhesion molecule-1 (VCAM-1) is a cell surface adhesion molecule involved in the recruitment of leukocytes to endothelial cells on arterial walls during the pathogenesis of atherosclerosis. The soluble ectodomain of VCAM-1 (sVCAM-1) is proteolytically released from the cell surface into the circulation, a process which is up-regulated in patients with cardiovascular or inflammatory disease. Here we investigate mechanisms involved in sVCAM-1 generation in response to cytokine stimulation. Methods: VCAM-1 ectodomain release into the conditioned media of MCEC-1 murine endothelial cells and cells grown from primary aortic explants from timp3−/− mice and wild-type littermates was measured by sandwich ELISA and Western blot after stimulation with tumor necrosis factor α (TNFα), interleukin-1β (IL-1β), or the phorbol ester PMA. Protease expression was inhibited (knocked down) with siRNA and validated using real-time PCR. Results: Proinflammatory cytokines IL-1β and TNFα up-regulated VCAM-1 ectodomain release from the MCEC-1 cells, and this was dependant on p38 and mitogen-activated protein kinases (MAP kinases) and inhibited by the matrix metalloproteinase (MMP) inhibitor BB94 and tissue inhibitor of metalloproteinase (TIMP)-3, but not TIMP-1 or TIMP-2. Timp-3−/− cells exhibited greater VCAM-1 ectodomain release following cytokine stimulation than TIMP-3-expressing cells. Additionally, cytokine stimulation of MCEC-1 cells was shown to cause down-regulation of TIMP-3 expression. Knockdown of the metalloproteinase ADAM17, but not ADAM10 or ADAM12, gene expression reduced cytokine-stimulated VCAM-1 shedding. Conclusions: TIMP-3 regulates the release of sVCAM-1 from cytokine-stimulated endothelial cells, which is mediated by ADAM17.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Dentistry
Publisher:	Oxford University Press
ISSN:	0008-6363
Date of Acceptance:	24 February 2005
Last Modified:	14 Sep 2023 14:45
URI:	https://orca.cardiff.ac.uk/id/eprint/161636

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