Related Experiment Videos
Interleukin-1 protects transformed keratinocytes from tumor necrosis factor-related apoptosis-inducing ligand
G Kothny-Wilkes1, D Kulms, B Pöppelmann
1Department of Dermatology, Ludwig Boltzmann Institute for Cell Biology and Immunobiology of the Skin, University of Münster, Von-Esmarchstrasse 56, D-48149 Münster, Germany.
Abstract:
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor family. It induces apoptosis primarily of transformed but not of normal cells and may therefore be a promising anti-cancer drug. Studying the role of TRAIL in apoptosis of keratinocytes, we detected TRAIL transcripts and protein in both normal human keratinocytes and transformed keratinocyte cell lines HaCaT and KB. Although normal keratinocytes were resistant to TRAIL, HaCaT and KB cells underwent apoptosis following TRAIL exposure. When HaCaT and KB cells were pretreated with the pro-inflammatory cytokine interleukin-1 (IL-1), cells became resistant to TRAIL-induced apoptosis. IL-1 significantly induced activation of the transcription factor NFkappaB in transformed keratinocytes. Moreover, the proteasome inhibitor MG132, which inhibits IL-1-induced NFkappaB activation, completely prevented the protective effect of IL-1. Thus, IL-1 appears to protect transformed keratinocytes from the cytotoxic effect of TRAIL via activation of NFkappaB. These data suggest that NFkappaB activation may protect cells from TRAIL-induced apoptosis and indicate a TRAIL receptor-independent pathway, which allows cells to escape the cytotoxic effect of TRAIL. Because IL-1 is secreted by a variety of tumor cells and is also released by inflammatory cells participating in the tumor-host immune response, tumors under these conditions could become resistant to TRAIL.
Insights
Interleukin-1 (IL-1) activates NF-kappaB, protecting transformed keratinocytes from tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced cell death. This suggests a mechanism for tumor resistance to TRAIL-based cancer therapies.
Area of Science:
- Cell Biology
- Molecular Oncology
- Immunology
Background:
- Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in transformed cells, showing potential as an anti-cancer drug.
- Keratinocytes, both normal and transformed, express TRAIL transcripts and protein.
- Normal keratinocytes are resistant to TRAIL, while transformed cell lines (HaCaT, KB) undergo apoptosis upon TRAIL exposure.
Purpose of the Study:
- To investigate the role of interleukin-1 (IL-1) in TRAIL-induced apoptosis of keratinocytes.
- To elucidate the signaling pathway involved in IL-1-mediated resistance to TRAIL.
- To understand potential mechanisms of tumor resistance to TRAIL therapy.
Main Methods:
- Detection of TRAIL transcripts and protein in normal and transformed keratinocytes.
- Exposure of keratinocytes to TRAIL and assessment of apoptosis.
- Pretreatment of cells with IL-1 and subsequent TRAIL exposure.
- Analysis of NF-kappaB activation using IL-1 stimulation.
- Inhibition of NF-kappaB activation with proteasome inhibitor MG132.
Main Results:
- IL-1 pretreatment rendered transformed keratinocytes resistant to TRAIL-induced apoptosis.
- IL-1 significantly induced activation of the transcription factor NF-kappaB in transformed keratinocytes.
- MG132, an inhibitor of NF-kappaB activation, completely blocked the protective effect of IL-1 against TRAIL.
- These findings suggest IL-1 protects transformed keratinocytes via NF-kappaB activation, independent of TRAIL receptor signaling.
Conclusions:
- NF-kappaB activation confers resistance to TRAIL-induced apoptosis in transformed keratinocytes.
- IL-1-mediated NF-kappaB activation represents a TRAIL receptor-independent escape mechanism from TRAIL-induced cytotoxicity.
- Tumors secreting IL-1 or involving inflammatory cells could develop resistance to TRAIL-based therapies.