Identification of IRF1 as critical dual regulator of Smac mimetic-induced apoptosis and inflammatory cytokine response.
Identification of IRF1 as critical dual regulator of Smac mimetic-induced apoptosis and inflammatory cytokine response.
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DOI：
10.1038/cddis.2014.498
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发表时间：
2014-12-11
影响因子：
9
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Smac （second mitochondria-derived activator of caspase）模拟物被认为是一种很有前景的抗癌治疗药物，它通过拮抗凋亡蛋白抑制剂来诱导细胞凋亡，而凋亡蛋白通常在癌细胞中大量表达。在这里，我们发现干扰素调节因子1 （IRF1）是一种新的关键调节剂，可以调节Smac模拟bv6诱导的细胞凋亡和促炎细胞因子分泌，影响免疫反应。IRF1敲低可挽救bv6诱导的细胞凋亡，并减弱bv6刺激的肿瘤坏死因子-α (TNFα)上调，表明IRF1至少在一定程度上通过诱导TNFα介导bv6触发的细胞死亡。这一观点得到了数据的支持，数据显示外源性TNFα的供应可以恢复bv6诱导的irf敲除细胞的细胞死亡。有趣的是，IRF1选择性地控制核因子-κB （NF-κB）靶基因的诱导，因为IRF1的耗尽减弱了bv6刺激的TNFα和白细胞介素-8 （IL-8）的上调，而不是p100和RelB。IRF1和p65的同时下调共同抑制bv6诱导的细胞死亡，暗示IRF1和NF-κB的协同相互作用。此外，IRF1的沉默阻碍了TNFα本身作为另一种典型的NF-κB刺激对TNFα的诱导。重要的是，IRF1的消耗阻碍了bv6刺激的其他促炎细胞因子的分泌，如粒细胞-巨噬细胞集落刺激因子（GM-CSF）、IL-8、IL-6和单核细胞化学引诱蛋白-1，以及原代单核细胞向bv6处理的肿瘤细胞的迁移。总之，IRF1作为bv6诱导的细胞凋亡和炎症细胞因子分泌的双重调节因子的鉴定，为Smac模拟物敏感性的决定因素以及Smac模拟物治疗对肿瘤微环境和免疫反应的可能影响提供了新的见解。
Smac (second mitochondria-derived activator of caspase) mimetics are considered as promising anticancer therapeutics and used to induce apoptosis by antagonizing inhibitor of apoptosis proteins, which are often abundantly expressed in cancer cells. Here, we identify interferon regulatory factor 1 (IRF1) as a novel critical regulator of Smac mimetic BV6-induced apoptosis and proinflammatory cytokine secretion with impact on the immune response. IRF1 knockdown rescues cells from BV6-induced apoptosis and attenuates BV6-stimulated upregulation of tumor necrosis factor-α (TNFα), indicating that IRF1 mediates BV6-triggered cell death, at least in part, by inducing TNFα. This notion is supported by data showing that exogenous supply of TNFα restores BV6-induced cell death in IRF-knockdown cells. Interestingly, IRF1 selectively controls the induction of nuclear factor-κB (NF-κB) target genes, as IRF1 depletion attenuates BV6-stimulated upregulation of TNFα and interleukin-8 (IL-8) but not p100 and RelB. Concomitant knockdown of IRF1 and p65 cooperate to inhibit BV6-induced cell death, implying a cooperative interaction of IRF1 and NF-κB. In addition, IRF1 silencing hampers TNFα induction by TNFα itself as an another prototypical NF-κB stimulus. Importantly, IRF1 depletion impedes BV6-stimulated secretion of additional proinflammatory cytokines such as granulocyte–macrophage colony-stimulating factor (GM-CSF), IL-8, IL-6 and monocyte chemoattractant protein-1, and migration of primary monocytes to BV6-treated tumor cells. In conclusion, this identification of IRF1 as a dual regulator of BV6-induced apoptosis and inflammatory cytokine secretion provides novel insights into determinants of sensitivity towards Smac mimetic and possible implications of Smac mimetic treatment on tumor microenvironment and immune response.