Molecular Cross-talk between the TRAIL and Interferon Signaling Pathways

Abstract

TRAIL/APO-2L induces apoptosis in a variety of transformed cells and has potential as an anti-cancer therapeutic. The physiologic role of TRAIL is presumably more complex than merely activating caspase-mediated cell death. To shed light into TRAIL-mediated signaling, we used DNA microarrays to profile gene expression mediated by TRAIL in breast carcinoma cells. Primary response genes induced by TRAIL included a number of known NF-B-dependent genes such as cIAP2, A20, and E-selectin. Remarkably, global transcriptome analysis revealed that TRAIL also induced a cohort of genes related to the interferon-signaling pathway. Assessing interferon-induced gene expression suggested various points of interaction with the TRAIL signaling pathway. Interestingly, while we observed interferon-mediated up-regulation of TRAIL, we also demonstrated a concomitant TRAIL-mediated induction of interferon-␤. Combining TRAIL and interferon in vitro, synergistically induced apoptosis and caspase activation in breast cancer cells. Together, these data indicate multiple levels of molecular cross-talk between the two diverse cytokines with anti-tumor properties.TRAIL/APO-2L is a member of the tumor necrosis factor (TNF) 1 cytokine family, which are type II transmembrane proteins that share homology in their extracellular domains (1-3). A subset of these ligands is known to activate the cell death program including TNF, Fas ligand, DR3 ligand (TWEAK), and TRAIL. Of these, TRAIL has garnered the most interest therapeutically, as several studies have demonstrated in vivo tumoricidal activity in animal models without significant toxicity (4 -6). Death ligands induce apoptosis by activating their cognate receptors on the surface of cells. These death receptors are members of the TNF receptor superfamily and include TNFRI, Fas (CD95/APO-1),

IFN-β Pretreatment Sensitizes Human Melanoma Cells to TRAIL/Apo2 Ligand-Induced Apoptosis

“…Unlike IFN-␣2 or IFN-␤, IFN-␥ may sensitize cells to DR-mediated apoptosis by up-regulation of DR5 (29). Similar observations regarding augmentation of TRAIL/Apo2L-induced apoptosis by IFN-␤ was reported in breast carcinoma cells (30). Very little cytotoxicity was observed with IFN-␤ or TRAIL/Apo2L alone or with the IFN-␤/TRAIL combination on primary nonmalignant human cells such as HUVECs, fibroblasts (HFF, WI-38), and astrocytes (CCF-TEN, CCF-BON).…”

T Cell TRAIL Promotes Murine Lupus by Sustaining Effector CD4 Th Cell Numbers and by Inhibiting CD8 CTL Activity

“…Type I IFNs are critical for up-regulation of TRAIL protein on T cells following TCR-mediated activation (43,44); however, TRAIL expression has also been shown to induce type I IFNs (48). To determine whether differential TRAIL up-regulation seen in acute and chronic GVHD mice (Fig.…”

Nod1 acts as an intracellular receptor to stimulate chemokine production and neutrophil recruitment in vivo

“…LoVo cells were treated with 2 μg/ml KF1B, AcMTP, 10 ng/ml TNFα, or left alone for the times indicated in the fi gures. Total RNA was prepared, and Cy3-and Cy5-labeled cDNA was synthesized from total RNA as described previously (43). Diff erential expression of 20,000 human genes (Invitrogen) was determined by hybridization of the probes with their cDNAs, followed by an analysis using a microarray scanner (GenePix 4000A; Molecular Devices) as described previously (43).…”