PMID:10903731

Citation	Kalina, U, Kauschat, D, Koyama, N, Nuernberger, H, Ballas, K, Koschmieder, S, Bug, G, Hofmann, WK, Hoelzer, D and Ottmann, OG (2000) IL-18 activates STAT3 in the natural killer cell line 92, augments cytotoxic activity, and mediates IFN-gamma production by the stress kinase p38 and by the extracellular regulated kinases p44erk-1 and p42erk-21. J. Immunol. 165:1307-13
Abstract	IL-18 is a regulator of NK cell function which utilizes the serine-threonine IL-1R-associated kinase signal transduction pathway and may activate additional not yet characterized signaling pathways. Here we evaluated IL-18-mediated signal transduction using the human NK cell line NK92 as a model. NK92 cells were shown by RT-PCR to express all three IL-18 receptor chains (IL-18R, accessory protein-like chain, IL-18-binding protein). Stimulation by IL-18 strongly enhanced tyrosine phosphorylation of STAT3 and of the mitogen-activated protein kinases (MAPK) p44erk-1and p42erk-2. In contrast, STAT5 was not activated. The cytolytic activity of NK92 against K562 target cells, which was augmented in a dose-dependent manner by IL-18 in the presence of trace amounts of IL-2, was suppressed by the specific inhibitors of MAPK pathways (PD098059 and SB203580). Similarly, the stimulatory effect of IL-18 on IFN-gamma protein production, given in conjunction with IL-2, was counteracted by inhibition of MAPK. IL-18 alone failed to stimulate IFN-gamma protein production despite inducing expression of IFN-gamma mRNA. IL-2 alone stimulated neither IFN-gamma mRNA expression nor IFN-gamma protein production. IL-18 did not stimulate proliferation of NK92 cells, either alone or in combination with IL-2 or IL-12. Inhibition of the MAPK pathway did not significantly alter the IL-2- and IL-12-induced proliferation of NK92 cells, whereas the Janus kinase/STAT pathway inhibitor AG490 strongly suppressed proliferation. MAPK activation appears to play a prominent role in IL-18 signaling, being involved in transcription and translation of IL-18-induced IFN-gamma mRNA and IL-18-induced cytolytic effects. In contrast, proliferation of NK92 cells is not affected by MAPK p44erk-1 and p42erk-2.
Links	PubMed
Keywords	Adjuvants, Immunologic/physiology; Cell Line/immunology; Cell Line/metabolism; Cytotoxicity, Immunologic/immunology; DNA-Binding Proteins/metabolism; Enzyme Activation/immunology; Humans; Interferon-gamma/antagonists & inhibitors; Interferon-gamma/biosynthesis; Interferon-gamma/genetics; Interleukin-18/biosynthesis; Interleukin-18/physiology; Killer Cells, Natural/enzymology; Killer Cells, Natural/immunology; Killer Cells, Natural/metabolism; Lymphocyte Activation/immunology; MAP Kinase Signaling System/immunology; Mitogen-Activated Protein Kinase 1/antagonists & inhibitors; Mitogen-Activated Protein Kinase 1/physiology; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases/antagonists & inhibitors; Mitogen-Activated Protein Kinases/physiology; Protein Binding/immunology; RNA, Messenger/biosynthesis; STAT3 Transcription Factor; Trans-Activators/metabolism; Up-Regulation/immunology; p38 Mitogen-Activated Protein Kinases
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:IL18		GO:0042517: positive regulation of tyrosine phosphorylation of Stat3 protein	ECO:0000314:		P		Fig 2 shows that stimulation of NK92 and NK92Ci cell lines with IL-18 results in activation and DNA binding of STAT3	complete CACAO 5399
HUMAN:IL18	involved_in	GO:0042531: positive regulation of tyrosine phosphorylation of STAT protein	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete

References

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