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Engagement of Fas differentially regulates the production of LPS ‐induced proinflammatory cytokines and type I interferons
Author(s) -
Brennan Kiva,
Lyons Caitriona,
Fernandes Philana,
Doyle Sarah,
Houston Aileen,
Brint Elizabeth
Publication year - 2019
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.14727
Subject(s) - fadd , proinflammatory cytokine , trif , signal transducing adaptor protein , microbiology and biotechnology , chemistry , death domain , fas ligand , luciferase , signal transduction , nf κb , biology , apoptosis , immune system , immunology , inflammation , toll like receptor , caspase , innate immune system , biochemistry , programmed cell death , transfection , gene
Fas ( CD 95) signalling is best known for its role in apoptosis, however, recent reports have shown it to be involved in other cellular responses as well, including inflammation. Fas and its adaptor protein FADD are known to negatively regulate LPS ‐induced proinflammatory responses, but their role in LPS ‐induced type I interferon production is unknown. Here, we demonstrate that Fas engagement on macrophages, using an agonistic Fas antibody CH 11, augments LPS ‐induced NF ‐κB responses, causing increased production of TNF α, IL ‐8, IL ‐6 and IL ‐12. Conversely, costimulation with both LPS and CH 11 causes a significant reduction in the level of interferon‐beta ( IFN β) production. This differential effect involves the Fas adaptor FADD because while LPS ‐induced IL ‐6 production increased in FADD −/− murine embryonic fibroblasts, LPS ‐induced IFN β production was significantly reduced in these cells. Overexpression of a dominant negative form of FADD ( FADD ‐ DD ) inhibits LPS ‐induced IFN β luciferase but not LPS ‐induced NF ‐κB luciferase. In contrast, overexpression of full‐length FADD inhibited LPS ‐induced NF ‐κB luciferase activation but was seen to augment LPS ‐induced IFN β luciferase. Moreover, FADD ‐ DD inhibits TRIF ‐, TRAM ‐, IKK ε‐, TBK ‐1‐ and TRAF 3‐induced IFN β luciferase production, with coimmunoprecipitation experiments demonstrating an interaction between FADD and TRIF . These data identify FADD as a novel component of the noncanonical Toll‐like receptor 4/ IFN β signalling pathway and demonstrate that both Fas and its adaptor FADD can differentially regulate the production of LPS ‐induced proinflammatory cytokines and type I interferons.