Wardle, D.J., Burgon, J., Sabroe, I. et al. (3 more authors) (2011) Effective caspase inhibition blocks neutrophil apoptosis and reveals Mcl-1 as both a regulator and a target of neutrophil caspase activation. Plos One, 6 (1). Art no.e15768. ISSN 1932-6203
Abstract
Human tissue inflammation is terminated, at least in part, by the death of inflammatory neutrophils by apoptosis. The regulation of this process is therefore key to understanding and manipulating inflammation resolution. Previous data have suggested that the short-lived pro-survival Bcl-2 family protein, Mcl-1, is instrumental in determining neutrophil lifespan. However, Mcl-1 can be cleaved following caspase activity, and the possibility therefore remains that the observed fall in Mcl-1 levels is due to caspase activity downstream of caspase activation, rather than being a key event initiating apoptosis in human neutrophils. We demonstrate that apoptosis in highly purified neutrophils can be almost completely abrogated by caspase inhibition with the highly effective di-peptide caspase inhibitor, Q-VD. OPh, confirming the caspase dependence of neutrophil apoptosis. Effective caspase inhibition does not prevent the observed fall in Mcl-1 levels early in ultrapure neutrophil culture, suggesting that this fall in Mcl-1 levels is not a consequence of neutrophil apoptosis. However, at later timepoints, declines in Mcl-1 can be reversed with effective caspase inhibition, suggesting that Mcl-1 is both an upstream regulator and a downstream target of caspase activity in human neutrophils.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2011 Wardle et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
Keywords: | Cell-Survival; Expression; Resolution; Cleavage; Inflammation; Receptor; Hypoxia; Death; Lipopolysaccharide; Granulocytes |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > The Medical School (Sheffield) > Department of Infection & Immunity The University of Sheffield > Faculty of Science (Sheffield) > School of Biosciences (Sheffield) > Department of Biomedical Science (Sheffield) > Centre for Developmental Genetics (Sheffield) The University of Sheffield > University of Sheffield Research Centres and Institutes > Centre for Developmental Genetics (Sheffield) |
Depositing User: | Miss Anthea Tucker |
Date Deposited: | 07 Mar 2011 16:13 |
Last Modified: | 10 Jun 2014 01:09 |
Published Version: | http://dx.doi.org/10.1371/journal.pone.0015768 |
Status: | Published |
Publisher: | Public Library Science |
Refereed: | Yes |
Identification Number: | 10.1371/journal.pone.0015768 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:42901 |