title: The proinflammatory cytokine interleukin-18 alters multiple signaling pathways to inhibit natural killer cell death.
abstract: The proinflammatory cytokine, interleukin-18 (IL-18), is a natural killer (NK) cell activator that induces NK cell cytotoxicity and interferon-gamma (IFN-gamma) expression. In this report, we define a novel role for IL-18 as an NK cell protective agent. Specifically, IL-18 prevents NK cell death initiated by different and distinct stress mechanisms. IL-18 reduces NK cell self-destruction during NK-targeted cell killing, and in the presence of staurosporin, a potent apoptotic inducer, IL-18 reduces caspase-3 activity. The critical regulatory step in this process is downstream of the mitochondrion and involves reduced cleavage and activation of caspase-9 and caspase-3. The ability of IL-18 to regulate cell survival is not limited to a caspase death pathway in that IL-18 augments tumor necrosis factor (TNF) signaling, resulting in increased and prolonged mRNA expression of c-apoptosis inhibitor 2 (cIAP2), a prosurvival factor and caspase-3 inhibitor, and TNF receptor-associated factor 1 (TRAF1), a prosurvival protein. The cumulative effects of IL-18 define a novel role for this cytokine as a molecular survival switch that functions to both decrease cell death through inhibition of the mitochondrial apoptotic pathway and enhance TNF induction of prosurvival factors.
authors.affiliation: Laboratory of Experimental Immunology, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD 21702-1201, USA.
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Hodge
authors.forename: Jeff J
authors.initials: JJ
authors.lastname: Subleski
authors.forename: Della A
authors.initials: DA
authors.lastname: Reynolds
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Buschman
authors.forename: William B
authors.initials: WB
authors.lastname: Schill
authors.forename: Mark W
authors.initials: MW
authors.lastname: Burkett
authors.forename: Anatoli M
authors.initials: AM
authors.lastname: Malyguine
authors.forename: Howard A
authors.initials: HA
authors.lastname: Young
mesh_terms: D017209:Apoptosis; D002478:Cells, Cultured; D006801:Humans; D018836:Inflammation Mediators / Q000494:pharmacology; D051034:Inhibitor of Apoptosis Proteins / Q000096:biosynthesis* / Q000235:genetics; D020382:Interleukin-18 / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D047990:TNF Receptor-Associated Factor 1 / Q000096:biosynthesis / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D018836:Inflammation Mediators; D051034:Inhibitor of Apoptosis Proteins; D020382:Interleukin-18; D016328:NF-kappa B; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D047990:TNF Receptor-Associated Factor 1; D014409:Tumor Necrosis Factor-alpha