Caspase inhibition prolongs inflammation by promoting a signaling complex with activated RIPK1.
J Cell Biol
; 220(6)2021 06 07.
Article
in En
| MEDLINE
| ID: mdl-33914027
ABSTRACT
Activation of inflammation by lipopolysaccharide (LPS) is an important innate immune response. Here we investigated the contribution of caspases to the LPS-mediated inflammatory response and discovered distinctive temporal roles of RIPK1 in mediating proinflammatory cytokine production when caspases are inhibited. We propose a biphasic model that differentiates the role of RIPK1 in early versus late phase. The early production of proinflammation cytokines stimulated by LPS with caspase inhibition is mediated by the NF-κB pathway that requires the scaffold function of RIPK1 but is kinase independent. Autocrine production of TNFα in the late phase promotes the formation of a novel TNFR1-associated complex with activated RIPK1, FADD, caspase-8, and key mediators of NF-κB signaling. The production of proinflammatory cytokines in the late phase can be blocked by RIPK1 kinase inhibitor Nec-1s. Our study demonstrates a mechanism by which the activation of RIPK1 promotes its own scaffold function to regulate the NF-κB-mediated proinflammatory cytokine production that is negatively regulated by caspases to restrain inflammatory signaling.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Cytokines
/
Caspase 8
/
Receptor-Interacting Protein Serine-Threonine Kinases
/
Caspase Inhibitors
/
Immunity, Innate
/
Inflammation
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
J Cell Biol
Year:
2021
Type:
Article
Affiliation country:
China