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  • Title: Disruption of NF-kappaB signaling reveals a novel role for NF-kappaB in the regulation of TNF-related apoptosis-inducing ligand expression.
    Author: Baetu TM, Kwon H, Sharma S, Grandvaux N, Hiscott J.
    Journal: J Immunol; 2001 Sep 15; 167(6):3164-73. PubMed ID: 11544302.
    Abstract:
    The NF-kappaB family of transcription factors functions broadly in the host control of immunoregulatory gene expression, inflammation, and apoptosis. Using Jurkat T cells engineered to inducibly express a transdominant repressor of IkappaBalpha, we examined the role of NF-kappaB in the regulation of cytokine and apoptotic gene expression. In this T cell model, as well as in primary T lymphocytes, expression of TNF-related apoptosis-inducing ligand (TRAIL) apoptotic signaling protein was dramatically down-regulated by inhibition of NF-kappaB binding activity. TRAIL acts through membrane death receptors to induce apoptosis of activated T lymphocytes and can be up-regulated by a variety of physiological and pharmacological inducers. However, regulation of TRAIL gene expression has not been defined. Treatment with TCR mimetics (PMA/ionomycin, PHA, and anti-CD3/CD28 Abs) resulted in a rapid increase in the expression of TRAIL mRNA and cell surface TRAIL protein. Induction of the transdominant repressor of IkappaBalpha dramatically down-regulated surface expression of TRAIL, indicating an essential role for NF-kappaB in the regulation of TRAIL. The induced expression of TRAIL was linked to a c-Rel binding site in the proximal TRAIL promoter at position -256 to -265; mutation of this site or an adjacent kappaB site resulted in a complete loss of the inducibility of the TRAIL promoter. The regulation of TRAIL expression by NF-kappaB may represent a general mechanism that contributes to the control of TRAIL-mediated apoptosis in T lymphocytes.
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