Regulation of Fas (CD95)-induced apoptosis by nuclear factor-κB and tumor necrosis factor-α in macrophages

Bin Lu, Liying Wang, Djordje Medan, David Toledo, Chuanshu Huang, Fei Chen, Xianglin Shi, Yon Rojanasakul

Research output: Contribution to journalArticlepeer-review

31 Scopus citations


The APO-1/Fas ligand (FasL) and tumor necrosis factor-α (TNF-α) 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-α, raising the possibility that TNF-α may be involved in FasL-induced apoptosis. Because TNF-α gene expression is under the control of nuclear factor-κB (NF-κB), we investigated whether FasL can induce NF-κB activation and whether such activation plays a role in FasL-mediated cell death in macrophages. Gene transfection studies using NF-κB-dependent reporter plasmid showed that FasL did activate NF-κB promoter activity. Gel shift studies also revealed that FasL mobilized the p50/p65 heterodimeric form of NF-κB. Inhibition of NF-κB by a specific NF-κB inhibitor, caffeic acid phenylethyl ester, or by dominant expression of the NF-κB inhibitory subunit IκB caused an increase in FasL-induced apoptosis and a reduction in TNF-α expression. However, neutralization of TNF-α by specific anti-TNF-α antibody had no effect on FasL-induced apoptosis. These results indicate that FasL-mediated cell death in macrophages is regulated through NF-κB and is independent of TNF-α activation, suggesting the antiapoptotic role of NF-κB and a separate death signaling pathway mediated by FasL.

Original languageEnglish
Pages (from-to)C831-C838
JournalAmerican Journal of Physiology - Cell Physiology
Issue number3 52-3
StatePublished - Sep 2002


  • Caspase-activated deoxyribonuclease
  • Tumor necrosis factor-α receptor

ASJC Scopus subject areas

  • Physiology
  • Cell Biology


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