Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) exerts a potent cytotoxic activity especially against many tumor cell types such as transformed keratinocytes. The specific role of the different TRAIL receptors in this process, however, is unknown. In this report we examine the role the TRAIL receptors play in both the apoptotic and nonapoptotic responses of HaCaT keratinocytes to leucine zipper TRAIL (LZ-TRAIL). By employing receptor-specific blocking antibodies we demonstrate that TRAIL receptor 1 plays the primary role in mediating caspase activation and apoptosis in HaCaT cells. Furthermore, we show that this receptor mainly mediates nuclear factor kappaB activation and expression of the pro-inflammatory cytokine interleukin-8 and that nuclear factor kappaB activation is critically required for the induction of pro-inflammatory cytokines in response to LZ-TRAIL. Taken together, our data suggest that beside its potent pro-apoptotic role, LZ-TRAIL leads to pro-inflammatory responses that are mainly mediated by TRAIL receptor 1 in HaCaT keratinocytes.