Regulation of Fas (CD95)-induced apoptosis by nuclear factor-KB and tumor necrosis factor- alpha in macrophages.
Lu-B; Wang-L; Medan-D; Toledo-D; Huang-C; Chen-F; Shi-X; Rojanasakul-Y
Am J Physiol, Cell Physiol 2002 Sep; 283(3):C831-C838
The APO-1/Fas ligand (FasL) and tumor necrosis factor-alpha (TNF-alpha) are two functionally related molecules that induce apoptosis of susceptible cells. Although the two molecules have been reported to induce apoptosis via distinct signaling pathways, we have shown that FasL can also upregulate the expression of TNF-alpha, raising the possibility that TNF-alpha may be involved in FasL-induced apoptosis. Because TNF-alpha gene expression is under the control of nuclear factor-KB (NF-KB), we investigated whether FasL can induce NF-KB activation and whether such activation plays a role in FasL-mediated cell death in macrophages. Gene transfection studies using NF-KB-dependent reporter plasmid showed that FasL did activate NF-KB promoter activity. Gel shift studies also revealed that FasL mobilized the p50/p65 heterodimeric form of NF-KB. Inhibition of NF-KB by a specific NF-KB inhibitor, caffeic acid phenylethyl ester, or by dominant expression of the NF-KB inhibitory subunit IKB caused an increase in FasL-induced apoptosis and a reduction in TNF-alpha expression. However, neutralization of TNF-alpha by specific anti-TNF-alpha antibody had no effect on FasL-induced apoptosis. These results indicate that FasL-mediated cell death in macrophages is regulated through NF-KB and is independent of TNF-alpha activation, suggesting the antiapoptotic role of NF-KB and a separate death signaling pathway mediated by FasL.
Cell-biology; Cell-damage; Cellular-function; Antibody-response; Tumor-inhibition; Deoxyribonucleic-acids; Enzyme-activity; Genes; Physiological-chemistry; Physiological-effects;
Author Keywords: tumor necrosis factor-alpha receptor; caspase-activated deoxyribonuclease
Y. Rojanasakul, Department of Basic Pharmaceutical Sciences, Health Sciences Center, West Virginia University, P.O. Box 9530, Morgantown, WV, 26506, USA
Research Tools and Approaches: Cancer Research Methods
American Journal of Physiology: Cell Physiology