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Effects of the cyclin-dependent kinase inhibitor R-roscovitine on eosinophil survival and clearance.

Farahi, N; Uller, Lena LU ; Juss, J K; Langton, A J; Cowburn, A S; Gibson, A; Foster, M R; Farrow, S N; Marco-Casanova, P and Sobolewski, A, et al. (2011) In Clinical and Experimental Allergy 41(5). p.673-687
Abstract
Background Eosinophils are pro-inflammatory cells implicated in the pathogenesis of asthma and atopy. Apoptosis has been proposed as a potential mechanism underlying the resolution of eosinophilic inflammation and studies have indicated the ability of interventions that induce human eosinophil apoptosis to promote the resolution of eosinophilic inflammation. Recently, the cyclin-dependent kinase (CDK) inhibitor R-roscovitine was shown to enhance neutrophil apoptosis and promote the resolution of neutrophilic inflammation. Objective The purpose of this study was to examine the expression of CDKs in human blood eosinophils, the effects of R-roscovitine on eosinophil survival in vitro and whether R-roscovitine could influence eosinophilic... (More)
Background Eosinophils are pro-inflammatory cells implicated in the pathogenesis of asthma and atopy. Apoptosis has been proposed as a potential mechanism underlying the resolution of eosinophilic inflammation and studies have indicated the ability of interventions that induce human eosinophil apoptosis to promote the resolution of eosinophilic inflammation. Recently, the cyclin-dependent kinase (CDK) inhibitor R-roscovitine was shown to enhance neutrophil apoptosis and promote the resolution of neutrophilic inflammation. Objective The purpose of this study was to examine the expression of CDKs in human blood eosinophils, the effects of R-roscovitine on eosinophil survival in vitro and whether R-roscovitine could influence eosinophilic lung inflammation in vivo. Methods Eosinophils were isolated from human peripheral blood and the effects of R-roscovitine on apoptosis, degranulation and phagocytic uptake examined in vitro. The effects of R-roscovitine on eosinophilic lung inflammation in vivo were also assessed using an ovalbumin mouse model. Results Our data demonstrate that human eosinophils express five known targets for R-roscovitine: CDK1, -2, -5, -7 and -9. R-roscovitine induced eosinophil apoptosis in a time- and concentration-dependent manner but also accelerated transition to secondary necrosis as assessed by microscopy, flow cytometry and caspase activation. In addition, we show that R-roscovitine can override the anti-apoptotic signals of GM-CSF and IL-5. We report that the pro-apoptotic effect of R-roscovitine is associated with suppression of Mcl-1L expression and that this compound enhanced phagocytic clearance of eosinophils by macrophages. Finally, we show that R-roscovitine induces apoptosis in murine peripheral blood and spleen-derived eosinophils; despite this, R-roscovitine did not modulate the tissue and lumen eosinophilia characteristic of the ovalbumin mouse model of airway eosinophilia. Conclusion and Clinical Relevance These data demonstrate that R-roscovitine is capable of inducing rapid apoptosis and secondary necrosis in eosinophils but does not affect the onset or improve the resolution of eosinophilic airway inflammation in vivo. (Less)
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publication status
published
subject
keywords
asthma, apoptosis, eosinophils
in
Clinical and Experimental Allergy
volume
41
issue
5
pages
673 - 687
publisher
Wiley-Blackwell
external identifiers
  • wos:000289482900011
  • pmid:21255143
  • scopus:79954497986
ISSN
1365-2222
DOI
10.1111/j.1365-2222.2010.03680.x
language
English
LU publication?
yes
id
74a35d0c-4760-421d-9fc6-a10d56b3cd91 (old id 1777137)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/21255143?dopt=Abstract
date added to LUP
2011-02-01 09:11:42
date last changed
2017-01-01 03:50:36
@article{74a35d0c-4760-421d-9fc6-a10d56b3cd91,
  abstract     = {Background Eosinophils are pro-inflammatory cells implicated in the pathogenesis of asthma and atopy. Apoptosis has been proposed as a potential mechanism underlying the resolution of eosinophilic inflammation and studies have indicated the ability of interventions that induce human eosinophil apoptosis to promote the resolution of eosinophilic inflammation. Recently, the cyclin-dependent kinase (CDK) inhibitor R-roscovitine was shown to enhance neutrophil apoptosis and promote the resolution of neutrophilic inflammation. Objective The purpose of this study was to examine the expression of CDKs in human blood eosinophils, the effects of R-roscovitine on eosinophil survival in vitro and whether R-roscovitine could influence eosinophilic lung inflammation in vivo. Methods Eosinophils were isolated from human peripheral blood and the effects of R-roscovitine on apoptosis, degranulation and phagocytic uptake examined in vitro. The effects of R-roscovitine on eosinophilic lung inflammation in vivo were also assessed using an ovalbumin mouse model. Results Our data demonstrate that human eosinophils express five known targets for R-roscovitine: CDK1, -2, -5, -7 and -9. R-roscovitine induced eosinophil apoptosis in a time- and concentration-dependent manner but also accelerated transition to secondary necrosis as assessed by microscopy, flow cytometry and caspase activation. In addition, we show that R-roscovitine can override the anti-apoptotic signals of GM-CSF and IL-5. We report that the pro-apoptotic effect of R-roscovitine is associated with suppression of Mcl-1L expression and that this compound enhanced phagocytic clearance of eosinophils by macrophages. Finally, we show that R-roscovitine induces apoptosis in murine peripheral blood and spleen-derived eosinophils; despite this, R-roscovitine did not modulate the tissue and lumen eosinophilia characteristic of the ovalbumin mouse model of airway eosinophilia. Conclusion and Clinical Relevance These data demonstrate that R-roscovitine is capable of inducing rapid apoptosis and secondary necrosis in eosinophils but does not affect the onset or improve the resolution of eosinophilic airway inflammation in vivo.},
  author       = {Farahi, N and Uller, Lena and Juss, J K and Langton, A J and Cowburn, A S and Gibson, A and Foster, M R and Farrow, S N and Marco-Casanova, P and Sobolewski, A and Condliffe, A M and Chilvers, E R},
  issn         = {1365-2222},
  keyword      = {asthma,apoptosis,eosinophils},
  language     = {eng},
  number       = {5},
  pages        = {673--687},
  publisher    = {Wiley-Blackwell},
  series       = {Clinical and Experimental Allergy},
  title        = {Effects of the cyclin-dependent kinase inhibitor R-roscovitine on eosinophil survival and clearance.},
  url          = {http://dx.doi.org/10.1111/j.1365-2222.2010.03680.x},
  volume       = {41},
  year         = {2011},
}