IRF9 is a Key Factor for Eliciting the Antiproliferative Activity of IFN-α

Abstract

A number of tumors are still resistant to the antiproliferative activity of human interferon (IFN)-α. The Janus kinases/Signal Transducers and Activators of Transcription (JAK-STAT) pathway plays an important role in initial IFN signaling. In order to enhance the antiproliferative activity of IFN-α, it is important to elucidate which factors in the JAK-STAT pathway play a key role in eliciting this activity. In human ovarian adenocarcinoma OVCAR3 cells sensitive to both IFN-α and -γ, only IFN regulatory factor 9 (IRF9)-RNA interference (RNAi) completely inhibited the antiproliferative activity of IFN-α among the intracellular JAK-STAT pathway factors. Conversely, Stat1-RNAi did not inhibit the antiproliferative activity of IFN-α, while it partially inhibited that of IFN-γ. As a cell death pathway, it is reported that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis via TRAIL-R (receptor) 1 and TRAIL-R2. In IFN-α-treated OVCAR3 cells, IRF9-RNAi inhibited transcription of TRAIL while Stat1-RNAi did not, suggesting that the transcription of TRAIL induced by IFN-α predominantly required IRF9. Furthermore, IFN-stimulated response element (ISRE)-like motifs of TRAIL bound to IFN-stimulated gene factor 3 (ISGF3) complex following IFN-α treatment. Subsequently, TRAIL-R2-RNAi inhibited both antiproliferative activities of IFN-α and TRAIL, suggesting that TRAIL-R2 mediated both IFN-α and TRAIL signals to elicit their antiproliferative activities. Finally, IRF9 overexpression facilitated IFN-α-induced apoptosis in T98G (human glioblastoma multiforme) cells, which were resistant to IFN-α. Thus, our present study suggests that IRF9 is the key factor for eliciting the antiproliferative activity of IFN-α and TRAIL may be one of the potential mediators.

Type-I interferon signaling through ISGF3 complex is required for sustained Rip3 activation and necroptosis in macrophages

“…In contrast to previous work (42), we have excluded a role for PKR in the induction of IFNAR1-dependent necroptosis. Further work will be necessary to elucidate the exact mechanism by which IRF9/ISGF3 sustains the activation of Rip3 at later time points, but here we add to recent work showing that IRF9 specifically mediates the antiproliferative and proapoptotic effects of IFN-α (43).…”

Identification of Alpha Interferon-Induced Genes Associated with Antiviral Activity in Daudi Cells and Characterization of IFIT3 as a Novel Antiviral Gene

“…Primers of ϳ20mer length (Table 1) were designed, and a three-step cycling protocol was performed as previously described (35). The results were analyzed by using MxPro software (version 4.01).…”

RNA interference and ovarian functions

“…Therefore, the small RNA interference-induced changes in ovarian hormones release and reception could be used for control of other, non-secretory ovarian functions. Some examples of control of ovarian proliferation and apoptosis through small RNA targeting hormones, growth factors (Rayhman et al, 2008;Li et al, 2009;Pierre et al, 2009;Wang et al, 2009b) and their receptors (Tsuda et al, 2005;Lu et al, 2008;Rayhman et al, 2008;Yotsumoto et al, 2008;Bruegmann et al, 2009;Chan et al, 2009;Donahue et al, 2009;Paragh et al, 2009;Pierre et al, 2009;Tian et al, 2009;Tsuno et al, 2009;Wang et al, 2009b) were present above.…”

“…IRF9-RNA and TRAIL receptor (TRAIL-R2)-RNA interference inhibited the anti-proliferative activity of IFN-alpha and TRAIL suggesting that these molecules could be potentially used for control of normal and malignant ovarian cells (Tsuno et al, 2009).…”