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      Cutting edge: FAS (CD95) mediates noncanonical IL-1β and IL-18 maturation via caspase-8 in an RIP3-independent manner.

      The Journal of Immunology Author Choice
      Animals, Antigens, CD95, physiology, Caspase 8, genetics, metabolism, Dendritic Cells, enzymology, immunology, Enzyme Activation, Fas-Associated Death Domain Protein, deficiency, Inflammasomes, Interleukin-18, biosynthesis, Interleukin-1beta, Macrophages, Peritoneal, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Receptor-Interacting Protein Serine-Threonine Kinases, Signal Transduction

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          Fas, a TNF family receptor, is activated by the membrane protein Fas ligand expressed on various immune cells. Fas signaling triggers apoptosis and induces inflammatory cytokine production. Among the Fas-induced cytokines, the IL-1β family cytokines require proteolysis to gain biological activity. Inflammasomes, which respond to pathogens and danger signals, cleave IL-1β cytokines via caspase-1. However, the mechanisms by which Fas regulates IL-1β activation remain unresolved. In this article, we demonstrate that macrophages exposed to TLR ligands upregulate Fas, which renders them responsive to receptor engagement by Fas ligand. Fas signaling activates caspase-8 in macrophages and dendritic cells, leading to the maturation of IL-1β and IL-18 independently of inflammasomes or RIP3. Hence, Fas controls a novel noncanonical IL-1β activation pathway in myeloid cells, which could play an essential role in inflammatory processes, tumor surveillance, and control of infectious diseases.

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