Regulation of Fas and Fas-ligand expression in NK cells by cytokines and the involvement of Fas-ligand in NK/LAK cell-mediated cytotoxicity.
This study demonstrates cytokine-mediated regulation of Fas and Fas-ligand (Fas-L) expression in human NK cells and the involvement of the Fas-L pathway in NK/LAK cytotoxicity. Freshly isolated, high purified human CD56+CD3- NK cells were found to express Fas and Fas-L. Cytokines further increased the Fas expression in the CD56+CD3- NK cells, with interleukin (IL)-2 being the most potent stimulus followed by IL-12, while IL-7 had no effect. IL-2 and IL-7 equally enhanced the Fas expression in the CD56+CD3+ population, while IL-12 had a less pronounced effect. Incubation of the CD56+CD3- NK cells with IL-2, but not with IL-12 and IL-7, led to an upregulation at the Fas-L expression, whereas neither of the cytokines affected the Fas-L expression in the CD56+CD3+ cells. Antagonistic Fas mAb M3 and Fas-IgG1 fusion protein significantly inhibited NK cytotoxicity towards Fas-expressing Jurkat cells, while non-antagonistic Fas mAb M31 and irrelevant CD14-IgG1 fusion protein had no effect. IL-2-generated LAK cells were much more potent than NK cells in exerting the cytotoxic effect on Jurkat cells, which was also partially inhibited to M3 and Fas-IgG1. Thus, human NK and LAK cells express Fas and Fas-L, utilize the Fas-L cytotoxic pathway and enhance the expression of these molecules in response to cytokines.
Medvedev
A E
AE
Institute of Cancer Research and Molecular Biology, Norwegian University of Science and Technology, Trondheim, Norway.
Johnsen
A C
AC
Haux
J
J
Steinkjer
B
B
Egeberg
K
K
Lynch
D H
DH
Sundan
A
A
Espevik
T
T
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001483:Base Sequence; D019002:CD56 Antigen / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D017931:DNA Primers / Q000235:genetics; D053222:Fas Ligand Protein; D006801:Humans; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000494:pharmacology; D019169:Jurkat Cells; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D019002:CD56 Antigen; D016207:Cytokines; D017931:DNA Primers; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D019014:fas Receptor