IL-2 activation of NK cells: involvement of MKK1/2/ERK but not p38 kinase pathway.
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-gamma 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.
Yu
T K
TK
Department of Cancer Biology, University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
Caudell
E G
EG
Smid
C
C
Grimm
E A
EA
D015703:Antigens, CD / Q000096:biosynthesis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis; D015415:Biomarkers; D004789:Enzyme Activation / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000276:immunology*; D015979:Killer Cells, Lymphokine-Activated / Q000201:enzymology / Q000276:immunology; D007694:Killer Cells, Natural / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D037181:Lectins, C-Type; D008213:Lymphocyte Activation / Q000276:immunology*; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D020935:MAP Kinase Signaling System / Q000276:immunology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases; D000099192:CD69 Antigens
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D015415:Biomarkers; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007371:Interferon-gamma; D007376:Interleukin-2; D037181:Lectins, C-Type; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011725:Pyridines; D015375:Receptors, Interleukin-2; D048051:p38 Mitogen-Activated Protein Kinases; D000099192:CD69 Antigens; C482128:MAP2K2 protein, human; C482125:MAP2K1 protein, human; C093642:SB 203580