Bacterial lipoprotein delays apoptosis in human neutrophils through inhibition of caspase-3 activity: regulatory roles for CD14 and TLR-2.
Authors
Power, Colm PWang, Jiang H
Manning, Brian
Kell, Malcolm R
Aherne, Noel J
Wu, Qiong D
Redmond, H Paul
Affiliation
Department of Academic Surgery, National University of Ireland, Cork University, Hospital. cjppower@yahoo.comIssue Date
2012-02-03T15:08:06ZMeSH
Antigens, CD14/*physiologyApoptosis/*drug effects
Bacterial Proteins/*pharmacology
Caspase 3
Caspases/*antagonists & inhibitors
Humans
Lipopolysaccharides/pharmacology
Lipoproteins/*pharmacology
Membrane Glycoproteins/*physiology
Membrane Potentials/drug effects
Neutrophils/cytology/*drug effects
Receptors, Cell Surface/*physiology
Toll-Like Receptor 2
Toll-Like Receptors
Metadata
Show full item recordCitation
J Immunol. 2004 Oct 15;173(8):5229-37.Journal
Journal of immunology (Baltimore, Md. : 1950)PubMed ID
15470068Abstract
The human sepsis syndrome resulting from bacterial infection continues to account for a significant proportion of hospital mortality. Neutralizing strategies aimed at individual bacterial wall products (such as LPS) have enjoyed limited success in this arena. Bacterial lipoprotein (BLP) is a major constituent of the wall of diverse bacterial forms and profoundly influences cellular function in vivo and in vitro, and has been implicated in the etiology of human sepsis. Delayed polymorphonuclear cell (PMN) apoptosis is a characteristic feature of human sepsis arising from Gram-negative or Gram-positive bacterial infection. Bacterial wall product ligation and subsequent receptor-mediated events upstream of caspase inhibition in neutrophils remain incompletely understood. BLP has been shown to exert its cellular effects primarily through TLR-2, and it is now widely accepted that lateral associations with the TLRs represent the means by which CD14 communicates intracellular messages. In this study, we demonstrate that BLP inhibits neutrophil mitochondrial membrane depolarization with a subsequent reduction in caspase-3 processing, ultimately leading to a significant delay in PMN apoptosis. Pretreatment of PMNs with an anti-TLR-2 mAb or anti-CD14 mAb prevented BLP from delaying PMN apoptosis to such a marked degree. Combination blockade using both mAbs completely prevented the effects of BLP (in 1 and 10 ng/ml concentrations) on PMN apoptosis. At higher concentrations of BLP, the antiapoptotic effects were observed, but were not as pronounced. Our findings therefore provide the first evidence of a crucial role for both CD14 and TLR-2 in delayed PMN apoptosis arising from bacterial infection.Language
engISSN
0022-1767 (Print)0022-1767 (Linking)
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