Bacterial lipoprotein delays apoptosis in human neutrophils through inhibition of caspase-3 activity: regulatory roles for CD14 and TLR-2.

Hdl Handle:
http://hdl.handle.net/10147/208944
Title:
Bacterial lipoprotein delays apoptosis in human neutrophils through inhibition of caspase-3 activity: regulatory roles for CD14 and TLR-2.
Authors:
Power, Colm P; Wang, 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.com
Citation:
J Immunol. 2004 Oct 15;173(8):5229-37.
Journal:
Journal of immunology (Baltimore, Md. : 1950)
Issue Date:
3-Feb-2012
URI:
http://hdl.handle.net/10147/208944
PubMed ID:
15470068
Abstract:
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:
eng
MeSH:
Antigens, CD14/*physiology; Apoptosis/*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
ISSN:
0022-1767 (Print); 0022-1767 (Linking)

Full metadata record

DC FieldValue Language
dc.contributor.authorPower, Colm Pen_GB
dc.contributor.authorWang, Jiang Hen_GB
dc.contributor.authorManning, Brianen_GB
dc.contributor.authorKell, Malcolm Ren_GB
dc.contributor.authorAherne, Noel Jen_GB
dc.contributor.authorWu, Qiong Den_GB
dc.contributor.authorRedmond, H Paulen_GB
dc.date.accessioned2012-02-03T15:08:06Z-
dc.date.available2012-02-03T15:08:06Z-
dc.date.issued2012-02-03T15:08:06Z-
dc.identifier.citationJ Immunol. 2004 Oct 15;173(8):5229-37.en_GB
dc.identifier.issn0022-1767 (Print)en_GB
dc.identifier.issn0022-1767 (Linking)en_GB
dc.identifier.pmid15470068en_GB
dc.identifier.urihttp://hdl.handle.net/10147/208944-
dc.description.abstractThe 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.en_GB
dc.language.isoengen_GB
dc.subject.meshAntigens, CD14/*physiologyen_GB
dc.subject.meshApoptosis/*drug effectsen_GB
dc.subject.meshBacterial Proteins/*pharmacologyen_GB
dc.subject.meshCaspase 3en_GB
dc.subject.meshCaspases/*antagonists & inhibitorsen_GB
dc.subject.meshHumansen_GB
dc.subject.meshLipopolysaccharides/pharmacologyen_GB
dc.subject.meshLipoproteins/*pharmacologyen_GB
dc.subject.meshMembrane Glycoproteins/*physiologyen_GB
dc.subject.meshMembrane Potentials/drug effectsen_GB
dc.subject.meshNeutrophils/cytology/*drug effectsen_GB
dc.subject.meshReceptors, Cell Surface/*physiologyen_GB
dc.subject.meshToll-Like Receptor 2en_GB
dc.subject.meshToll-Like Receptorsen_GB
dc.titleBacterial lipoprotein delays apoptosis in human neutrophils through inhibition of caspase-3 activity: regulatory roles for CD14 and TLR-2.en_GB
dc.contributor.departmentDepartment of Academic Surgery, National University of Ireland, Cork University, Hospital. cjppower@yahoo.comen_GB
dc.identifier.journalJournal of immunology (Baltimore, Md. : 1950)en_GB
dc.description.provinceMunster-

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