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Department of Cancer Biology, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030
IL-2 stimulates extracellular signal-regulated protein kinase (ERK)
and p38 mitogen-activated protein kinase (MAPK) in various immune cell
populations. The functional roles that these kinases play are still
unclear. In this study, we examined whether MAPK kinase (MKK)/ERK and
p38 MAPK pathways are necessary for IL-2 to activate NK cells. Using
freshly isolated human NK cells, we established that an intact MKK/ERK
pathway is necessary for IL-2 to activate NK cells to express at least
four known biological responses: LAK generation, IFN-
secretion, and
CD25 and CD69 expression. IL-2 induced ERK activation within 5 min.
Treatment of NK cells with a specific inhibitor of MKK1/2, PD98059,
during the IL-2 stimulation blocked in a dose-dependent manner each of
four sequelae, with inhibition of lymphokine-activated killing
induction being least sensitive to MKK/ERK pathway blockade. Activation
of p38 MAPK by IL-2 was not detected in NK cells. In contrast to what
was observed by others in T lymphocytes, SB203850, a specific inhibitor
of p38 MAPK, did not inhibit IL-2-activated NK functions. This data
indicate that p38 MAPK activation was not required for IL-2 to activate
NK cells for the four functions examined. These results reveal
selective signaling differences between NK cells and T lymphocytes; in
NK cells, the MKK/ERK pathway and not p38 MAPK plays a critical
positive regulatory role during activation by
IL-2.
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