Interleukin-1 protects transformed keratinocytes from tumor necrosis factor-related apoptosis-inducing ligand.

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.