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Journal of Interferon & Cytokine Research

The Proinflammatory Cytokine Interleukin-18 Alters Multiple Signaling Pathways to Inhibit Natural Killer Cell Death

To cite this article:
Deborah L. Hodge, Jeff J. Subleski, Della A. Reynolds, Matthew D. Buschman, William B. Schill, Mark W. Burkett, Anatoli M. Malyguine, and Dr. Howard A. Young. Journal of Interferon & Cytokine Research. October 2006, 26(10): 706-718. https://doi.org/10.1089/jir.2006.26.706

Published in Volume: 26 Issue 10: October 10, 2006

Author information

Deborah L. Hodge
Laboratory of Experimental Immunology, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD 21702-1201.
Jeff J. Subleski
Laboratory of Experimental Immunology, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD 21702-1201.
Della A. Reynolds
Laboratory of Experimental Immunology, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD 21702-1201.
Matthew D. Buschman
Laboratory of Experimental Immunology, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD 21702-1201.
William B. Schill
National Fish Health Research, Laboratory, U.S. Geological Survey-Leetown Science Center, Kearneysville, WV 25430.
Mark W. Burkett
Clinical Services Program, Science Applications International Corporation, Frederick, MD 21702-1201.
Anatoli M. Malyguine
Clinical Services Program, Science Applications International Corporation, Frederick, MD 21702-1201.
Dr. Howard A. Young
Laboratory of Experimental Immunology, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD 21702-1201.

ABSTRACT

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

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