The proinflammatory cytokine interleukin-18 alters multiple signaling pathways to inhibit natural killer cell death

Hodge, D. L.; Subleski, J. J.; Reynolds, D. A.; Buschman, M. D.; Schill, W. B.; Burkett, M. W.; Malyguine, A. M.; Young, H. A.

Abstract:

The proinflammatory cytokine, interleukin-18 (IL-18), is a natural killer (NK) cell activator that induces NK cell cytotoxicity and interferon-?? (IFN-??) 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. ?? Mary Ann Liebert, Inc.

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Article

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70028280

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Hodge, D. L.; Subleski, J. J.; Reynolds, D. A.; Buschman, M. D.; Schill, W. B.; Burkett, M. W.; Malyguine, A. M.; Young, H. A.

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718

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English

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Journal of Interferon and Cytokine Research

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The proinflammatory cytokine interleukin-18 alters multiple signaling pathways to inhibit natural killer cell death; 2006; Article; Journal; Journal of Interferon and Cytokine Research; Hodge, D. L.; Subleski, J. J.; Reynolds, D. A.; Buschman, M. D.; Schill, W. B.; Burkett, M. W.; Malyguine, A. M.; Young, H. A.