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A RIPK3-caspase 8 complex mediates atypical pro-IL-1ß processing.
Moriwaki, Kenta; Bertin, John; Gough, Peter J; Chan, Francis Ka-Ming.
Afiliação
  • Moriwaki K; Department of Pathology, Program in Immunology & Microbiology, University of Massachusetts Medical School, Worcester, MA 01655; and.
  • Bertin J; Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA 19422.
  • Gough PJ; Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA 19422.
  • Chan FK; Department of Pathology, Program in Immunology & Microbiology, University of Massachusetts Medical School, Worcester, MA 01655; and francis.chan@umassmed.edu.
J Immunol ; 194(4): 1938-44, 2015 Feb 15.
Article em En | MEDLINE | ID: mdl-25567679
Caspase 8, the initiator caspase for death receptor-induced apoptosis, functions as a negative regulator of receptor interacting protein kinase 3 (RIPK3), an essential factor for TNF-, TLR3-, and TLR4-induced necroptosis. In certain situations, caspase 8 can also participate in pro-IL-1ß processing. However, the biochemical complex that mediates caspase 8-mediated processing is not defined. In this study, we show that RIPK3 is crucial for caspase 1- and caspase 8-mediated pro-IL-1ß and pro-IL-18 processing in bone marrow-derived dendritic cells (BMDCs) in response to LPS stimulation. Caspase 8-mediated pro-IL-1ß processing requires intact RIPK1, RIPK3, TRIF, and FADD. In response to LPS, a complex that contains RIPK1, RIPK3, FADD, and caspase 8 is formed. Surprisingly, RIPK3-specific kinase inhibitors strongly enhanced caspase 8 activation and pro-IL-1ß processing in LPS-stimulated BMDCs. However, studies in BMDCs expressing the kinase-inactive RIPK3-K51A mutant or RIPK1-K45A mutant showed that the kinase activity of neither RIPK1 nor RIPK3 is required for LPS-induced caspase 8 activation and IL-1ß secretion. Hence, RIPK3 is an unexpected positive regulator of caspase 8 activity that promotes IL-1ß maturation in BMDCs.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Células Dendríticas / Caspase 8 / Proteína Serina-Treonina Quinases de Interação com Receptores / Interleucina-1beta Limite: Animals Idioma: En Revista: J Immunol Ano de publicação: 2015 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Células Dendríticas / Caspase 8 / Proteína Serina-Treonina Quinases de Interação com Receptores / Interleucina-1beta Limite: Animals Idioma: En Revista: J Immunol Ano de publicação: 2015 Tipo de documento: Article