Tumor necrosis factor-alpha and interferon-gamma induce expression of functional Fas ligand on HT29 and MCF7 adenocarcinoma cells.
Tumor cells develop diverse mechanisms to escape from immune surveillance, including expression of Fas ligand (FasL), a 40-kDa type II transmembrane protein that mediates apoptosis by binding to its cognate receptor Fas (APO-1/CD95). Upon activation, T lymphocytes and natural killer (NK) cells express Fas and thus become sensitive to FasL-mediated apoptosis. Here we show that tumor necrosis factor-alpha (TNF-alpha) in addition to interferon-gamma (IFN-gamma) induces cell surface expression of functional FasL in human HT29 colon and MCF7 breast adenocarcinoma cells that constitutively lack cell surface expression of FasL. These cells, expressing FasL, are capable of inducing apoptosis in Fas-positive Jurkat T cells mediated by plasma membrane-bound FasL and soluble forms of FasL. By contrast, mutational deletion of Fas cell surface expression as well as inhibition of caspase family proteases involved in Fas signaling and monoclonal antibodies neutralizing FasL protect Jurkat T cells from apoptosis caused by the FasL-expressing HT29 or MCF7 cells. These results demonstrate that TNF-alpha and IFN-gamma induce expression of functional FasL in adenocarcinoma cells which thereby can kill T lymphocytes by the FasL/Fas pathway.
Naujokat
C
C
Universitätsklinikum Charité, Medizinische Fakultät der Humboldt-Universität Berlin, Schumannstrabetae 20/21, Berlin, 10098, Germany. cord.naujokat@urz.uni-heidelberg.de
Sezer
O
O
Possinger
K
K
D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D053222:Fas Ligand Protein; D019073:HT29 Cells; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000096:biosynthesis*; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000970:Antineoplastic Agents; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma