Data/hora: 01/06/2024 02:25:43

Provedor de dados: 	17	
País: 	United Kingdom	
Título: 	Circulating Neutrophils from Trauma Patients Induce Apoptosis Through Dephosphorylation of Epithelial Cell Caspase-8	
Autores: 	Songhui Jia; Jean Parodo; Emmanuel Battisti-Charbonney; Jennifer Tsang; Sangyang Jia; Ori D. Rotstein; Andras Kapus; John C. Marshall.	
Data: 	2011-09-12	
Ano: 	2011	
Palavras-chave: 	Immunology.	
Resumo: 	Activated neutrophils can cause oxidant-mediated bystander injury to host cells. This injury has previously been ascribed to the direct effects of oxidants on membrane phospholipids. We show here that oxidants released by neutrophils activated in vivo in survivors of multiple trauma or in vitro by exposure to bacterial lipopolysaccharide (LPS) can also promote the apoptotic death of epithelial cells, through the SHP-1-mediated dephosphorylation of epithelial cell caspase-8. Neutrophils from a cohort of patients who sustained serious injury induced the apoptotic death of cultured epithelial cells in a manner that was dependent on the activity of the NADPH oxidase and the generation of neutrophil-derived reactive oxygen intermediates. Caspase-8 is constitutively tyrosine phosphorylated in a panel of resting epithelial cells, but undergoes dephosphorylation in response to hydrogen peroxide (H2O2), activated neutrophils, or inhibition of Src kinases. Mutation of either of 2 key caspase-8 tyrosine residues, Y397 and Y465 to a non-phosphorylatable phenylalanine accelerates the apoptosis of epithelial cells transfected with caspase-8, while mutation of the same tyrosine residues to the phosphomimetic glutamic acid, or transfection with the Src kinases Lyn or c-Src inhibits H2O2-induced apoptosis. Exposure to either H2O2 or LPS-stimulated neutrophils, increases the phosphorylation and activity of the phosphatase SHP-1, increases the activity of caspases-8 and -3, and accelerates epithelial cell apoptosis. Together these data reveal a novel mechanism for neutrophil-mediated tissue injury through oxidant-dependent SHP-1-mediated dephosphorylation of caspase-8 resulting in enhanced epithelial cell apoptosis.	
Tipo: 	Manuscript	
Identificador: 	http://precedings.nature.com/documents/6393/version/1

oai:nature.com:10101/npre.2011.6393.1

http://hdl.handle.net/10101/npre.2011.6393.1	
Fonte: 	Nature Precedings	
Fonte: 	Creative Commons Attribution 3.0 License