Linked Life Data

15383576

Source:http://linkedlifedata.com/resource/pubmed/id/15383576

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
7
pubmed:dateCreated
2004-9-22
pubmed:abstractText
Depletion of dendritic cells (DCs) via apoptosis contributes to sepsis-induced immune suppression. The mechanisms leading to DC apoptosis during sepsis are not known. In this study we report that immature DCs undergo apoptosis when treated with high numbers of Escherichia coli. This effect was mimicked by high concentrations of LPS. Apoptosis was accompanied by generation of ceramide through activation of acid sphingomyelinase (A-SMase), was prevented by inhibitors of this enzyme, and was restored by exogenous ceramide. Compared with immature DCs, mature DCs expressed significantly reduced levels of A-SMase, did not generate ceramide in response to E. coli or LPS, and were insensitive to E. coli- and LPS-triggered apoptosis. However, sensitivity to apoptosis was restored by addition of exogenous A-SMase or ceramide. Furthermore, inhibition of A-SMase activation and ceramide generation was found to be the mechanism through which the immune-modulating messenger NO protects immature DCs from the apoptogenic effects of E. coli and LPS. NO acted through formation of cGMP and stimulation of the cGMP-dependent protein kinase. The relevance of A-SMase and its inhibition by NO/cGMP were confirmed in a mouse model of LPS-induced sepsis. DC apoptosis was significantly higher in inducible NO synthase-deficient mice than in wild-type animals and was significantly reduced by treatment ex vivo with NO, cGMP, or the A-SMase inhibitor imipramine. Thus, A-SMase plays a central role in E. coli/LPS-induced DC apoptosis and its inhibition by NO, and it might be a target of new therapeutic approaches to sepsis.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
AIM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Oct
pubmed:issn
0022-1767
pubmed:author
pubmed:issnType
Print
pubmed:day
1
pubmed:volume
173
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
4452-63
pubmed:dateRevised
2011-10-27
pubmed:meshHeading
pubmed-meshheading:15383576-Animals, pubmed-meshheading:15383576-Apoptosis, pubmed-meshheading:15383576-Cell Differentiation, pubmed-meshheading:15383576-Cells, Cultured, pubmed-meshheading:15383576-Ceramides, pubmed-meshheading:15383576-Cyclic GMP, pubmed-meshheading:15383576-Dendritic Cells, pubmed-meshheading:15383576-Dose-Response Relationship, Immunologic, pubmed-meshheading:15383576-Enzyme Activation, pubmed-meshheading:15383576-Escherichia coli, pubmed-meshheading:15383576-Female, pubmed-meshheading:15383576-Humans, pubmed-meshheading:15383576-Immunity, Innate, pubmed-meshheading:15383576-Lipopolysaccharides, pubmed-meshheading:15383576-Mice, pubmed-meshheading:15383576-Mice, Inbred C57BL, pubmed-meshheading:15383576-Mice, Knockout, pubmed-meshheading:15383576-Nitric Oxide, pubmed-meshheading:15383576-Nitric Oxide Synthase, pubmed-meshheading:15383576-Nitric Oxide Synthase Type II, pubmed-meshheading:15383576-Sepsis, pubmed-meshheading:15383576-Signal Transduction, pubmed-meshheading:15383576-Sphingomyelin Phosphodiesterase
pubmed:year
2004
pubmed:articleTitle
Activation of acid sphingomyelinase and its inhibition by the nitric oxide/cyclic guanosine 3',5'-monophosphate pathway: key events in Escherichia coli-elicited apoptosis of dendritic cells.
pubmed:affiliation
Vita-Salute University and Stem Cell Research Institute, San Raffaele, Milan, Italy.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't