IL-18 activates STAT3 in the natural killer cell line 92, augments cytotoxic activity, and mediates IFN-gamma production by the stress kinase p38 andby the extracellular regulated kinases p44(erk-1) and p42(erk-21)
U. Kalina et al., IL-18 activates STAT3 in the natural killer cell line 92, augments cytotoxic activity, and mediates IFN-gamma production by the stress kinase p38 andby the extracellular regulated kinases p44(erk-1) and p42(erk-21), J IMMUNOL, 165(3), 2000, pp. 1307-1313
IL-18 is a regulator of NK cell function which utilizes the serine-threonin
e IL-1R-associated kinase signal transduction pathway and may activate addi
tional not yet characterized signaling pathways. Here we evaluated IL-18-me
diated signal transduction using the human NK cell line NK92 as a model. NK
92 cells were shown by RT-PCR to express all three IL-18 receptor chains (I
L-18R, accessory protein-like chain, IL-18-binding protein). Stimulation by
IL-18 strongly enhanced tyrosine phosphorylation of STAT3 and of the mitog
en-activated protein kinases (MAPK) p44(erk-1) and p42(erk-2). In contrast,
STAT5 was not activated, The cytolytic activity of NK92 against K562 targe
t cells, which was augmented in a dose-dependent manner by IL-18 in the pre
sence of trace amounts of IL-2, was suppressed by the specific inhibitors o
f MAPK pathways (PD098059 and SB203580), Similarly, the stimulatory effect
of IL-18 on IFN-gamma protein production, given in conjunction with IL-2, w
as 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 alo
ne 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 suppr
essed proliferation MAPK activation appears to play a prominent role in IL-
18 signaling, being involved in transcription and translation of IL-18-indu
ced IFN-gamma mRNA and IL-18-induced cytolytic effects. In contrast, prolif
eration of NK92 cells is not affected by MAPK p44(erk-1) and p42(erk-2).