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Effective Caspase Inhibition Blocks Neutrophil Apoptosis and Reveals Mcl-1 as Both a Regulator and a Target of Neutrophil Caspase Activation

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  • David J. Wardle
  • Joseph Burgon
  • Ian Sabroe
  • Colin D. Bingle
  • Moira K. B. Whyte
  • Stephen A. Renshaw

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    Rights statement: Copyright: © 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.

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http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0015768
Original languageEnglish
Article number15768
Number of pages7
JournalPLoS ONE
Volume6
Issue number1
DOIs
Publication statusPublished - 6 Jan 2011

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.

    Research areas

  • CELL-SURVIVAL, EXPRESSION, RESOLUTION, CLEAVAGE, INFLAMMATION, RECEPTOR, HYPOXIA, DEATH, LIPOPOLYSACCHARIDE, GRANULOCYTES

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