IL-2 activation of NK cells: involvement of MKK1/2/ERK but not p38 kinase pathway

J Immunol. 2000 Jun 15;164(12):6244-51. doi: 10.4049/jimmunol.164.12.6244.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antigens, CD / biosynthesis
  • Antigens, Differentiation, T-Lymphocyte / biosynthesis
  • Biomarkers
  • Enzyme Activation / immunology
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Imidazoles / pharmacology
  • Interferon-gamma / metabolism
  • Interleukin-2 / immunology*
  • Killer Cells, Lymphokine-Activated / enzymology
  • Killer Cells, Lymphokine-Activated / immunology
  • Killer Cells, Natural / enzymology*
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism
  • Lectins, C-Type
  • Lymphocyte Activation / immunology*
  • MAP Kinase Kinase 1
  • MAP Kinase Kinase 2
  • MAP Kinase Signaling System / immunology*
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Mitogen-Activated Protein Kinase Kinases / physiology
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / metabolism
  • Mitogen-Activated Protein Kinases / physiology
  • Protein Serine-Threonine Kinases / metabolism
  • Protein Serine-Threonine Kinases / physiology
  • Protein-Tyrosine Kinases / metabolism
  • Protein-Tyrosine Kinases / physiology
  • Pyridines / pharmacology
  • Receptors, Interleukin-2 / biosynthesis
  • p38 Mitogen-Activated Protein Kinases

Substances

  • Antigens, CD
  • Antigens, Differentiation, T-Lymphocyte
  • Biomarkers
  • CD69 antigen
  • Enzyme Inhibitors
  • Imidazoles
  • Interleukin-2
  • Lectins, C-Type
  • Pyridines
  • Receptors, Interleukin-2
  • Interferon-gamma
  • MAP2K2 protein, human
  • Protein-Tyrosine Kinases
  • Protein Serine-Threonine Kinases
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 1
  • MAP Kinase Kinase 2
  • MAP2K1 protein, human
  • Mitogen-Activated Protein Kinase Kinases
  • SB 203580