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Production by the Stress Kinase p38 and by the Extracellular Regulated Kinases p44erk-1 and p42erk-21
Department of Hematology, Johann Wolfgang Goethe University Hospital, Frankfurt/Main, Germany
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-
protein production, given in conjunction with IL-2,
was counteracted by inhibition of MAPK. IL-18 alone failed to stimulate
IFN- protein production despite inducing expression of IFN- mRNA.
IL-2 alone stimulated neither IFN- mRNA expression nor IFN-
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- mRNA and IL-18-induced cytolytic effects. In contrast,
proliferation of NK92 cells is not affected by MAPK
p44erk-1 and
p42erk-2.
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