Regulation of p38 mitogen-activated protein kinase during NK cell activation.
The mitogen-activated protein kinase (MAPK) p38 modulates a variety of cellular functions, including proliferation, differentiation and cell death. However, we report here a novel function for p38, i.e. the regulation of cytotoxic lymphocyte-mediated cytotoxicity. Stimulation of NK cells by either cross-linking of their FcgammaRIII receptors or by binding to NK-sensitive target cells induces the phosphorylation and activation of p38, and also of its upstream regulators MKK3/MKK6. Pharmacologic analyses suggest that Src-family and Syk-family protein tyrosine kinases couple the NK cell surface receptors to p38 activation. The role of p38 in the cytotoxic function of NK cells was tested by treatment of NK cells with the cell-permeable, p38-specific inhibitor SB203580. Interestingly, exposure to the drug reduced both antibody-dependent cellular cytotoxicity and natural cytotoxicity, but maximal inhibitory concentrations resulted in only partial inhibition. Collectively, these results suggest that the p38 MAPK pathway is stimulated during the development of NK cell-mediated cytotoxicity and that efficient killing is influenced by both p38-dependent and p38-independent pathways. More broadly, this study identifies the regulation of cell-mediated killing as a novel role for p38 in cytotoxic lymphocytes.
Chini
C C
CC
Department of Immunology, Mayo Graduate and Medical Schools, Mayo Clinic, Rochester 55905, USA.
Boos
M D
MD
Dick
C J
CJ
Schoon
R A
RA
Leibson
P J
PJ
D000730:Androstadienes / Q000494:pharmacology; D000920:Antibody-Dependent Cell Cytotoxicity / Q000502:physiology; D003602:Cytotoxicity, Immunologic / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004792:Enzyme Precursors / Q000502:physiology; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D007694:Killer Cells, Natural / Q000201:enzymology* / Q000276:immunology; D008213:Lymphocyte Activation; D020935:MAP Kinase Signaling System; D008301:Maleimides / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011499:Protein Processing, Post-Translational; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology; D017452:Receptors, IgG / Q000276:immunology; D000072377:Syk Kinase; D000077191:Wortmannin; D048051:p38 Mitogen-Activated Protein Kinases; D019061:src-Family Kinases / Q000502:physiology
D000730:Androstadienes; D004791:Enzyme Inhibitors; D004792:Enzyme Precursors; D005419:Flavonoids; D007093:Imidazoles; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; D008301:Maleimides; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines; D017452:Receptors, IgG; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; D019061:src-Family Kinases; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C070515:bisindolylmaleimide I; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D000077191:Wortmannin