RIP kinase-dependent necrosis drives lethal systemic inflammatory response syndrome.
Immunity
; 35(6): 908-18, 2011 Dec 23.
Article
em En
| MEDLINE
| ID: mdl-22195746
ABSTRACT
Engagement of tumor necrosis factor receptor 1 signals two diametrically opposed pathways survival-inflammation and cell death. An additional switch decides, depending on the cellular context, between caspase-dependent apoptosis and RIP kinase (RIPK)-mediated necrosis, also termed necroptosis. We explored the contribution of both cell death pathways in TNF-induced systemic inflammatory response syndrome (SIRS). Deletion of apoptotic executioner caspases (caspase-3 or -7) or inflammatory caspase-1 had no impact on lethal SIRS. However, deletion of RIPK3 conferred complete protection against lethal SIRS and reduced the amounts of circulating damage-associated molecular patterns. Pretreatment with the RIPK1 kinase inhibitor, necrostatin-1, provided a similar effect. These results suggest that RIPK1-RIPK3-mediated cellular damage by necrosis drives mortality during TNF-induced SIRS. RIPK3 deficiency also protected against cecal ligation and puncture, underscoring the clinical relevance of RIPK kinase inhibition in sepsis and identifying components of the necroptotic pathway that are potential therapeutic targets for treatment of SIRS and sepsis.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Síndrome de Resposta Inflamatória Sistêmica
/
Proteína Serina-Treonina Quinases de Interação com Receptores
/
Necrose
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2011
Tipo de documento:
Article