PDF(Pubmed)
Abstract：
Hyperinflammation is the hallmark of Kaposi\'s sarcoma (KS), the most common cancer in AIDS patients caused by Kaposi\'s sarcoma-associated herpesvirus (KSHV) infection. However, the role and mechanism of induction of inflammation in KS remain unclear. In a screening for inhibitors of KSHV-induced oncogenesis, over half of the identified candidates were anti-inflammatory agents including dexamethasone functions by activating glucocorticoid receptor (GR) signaling. Here, we examined the mechanism mediating KSHV-induced inflammation. We found that numerous inflammatory pathways were activated in KSHV-transformed cells. Particularly, interleukin-1 alpha (IL-1α) and IL-1 receptor antagonist (IL-1Ra) from the IL-1 family were the most induced and suppressed cytokines, respectively. We found that KSHV miRNAs mediated IL-1α induction while both miRNAs and vFLIP mediated IL-1Ra suppression. Furthermore, GR signaling was inhibited in KSHV-transformed cells, which was mediated by vFLIP and vCyclin. Dexamethasone treatment activated GR signaling, and inhibited cell proliferation and colony formation in soft agar of KSHV-transformed cells but had a minimal effect on matched primary cells. Consequently, dexamethasone suppressed the initiation and growth of KSHV-induced tumors in mice. Mechanistically, dexamethasone suppressed IL-1α but induced IL-1Ra expression. Treatment with recombinant IL-1α protein rescued the inhibitory effect of dexamethasone while overexpression of IL-1Ra caused a weak growth inhibition of KSHV-transformed cells. Furthermore, dexamethasone induced IκBα expression resulting in inhibition of NF-κB pathway and IL-1α expression. These results reveal an important role of IL-1 pathway in KSHV-induced inflammation and oncogenesis, which can be inhibited by dexamethasone-activated GR signaling, and identify IL-1-mediated inflammation as a potential therapeutic target for KSHV-induced malignancies.
摘要：
炎症过度是卡波西肉瘤（KS）的标志，艾滋病患者中最常见的癌症是由卡波西肉瘤相关疱疹病毒（KSHV）感染引起的。然而,炎症诱导在KS中的作用和机制尚不清楚。在筛选KSHV诱导的肿瘤发生的抑制剂中，超过一半的候选药物是抗炎药,包括通过激活糖皮质激素受体(GR)信号发挥功能的地塞米松.这里,我们研究了介导KSHV诱导的炎症的机制。我们发现许多炎症途径在KSHV转化的细胞中被激活。特别是,白细胞介素-1α(IL-1α)和IL-1受体拮抗剂(IL-1Ra)是IL-1家族中诱导和抑制最多的细胞因子,分别。我们发现KSHVmiRNA介导IL-1α诱导，而miRNA和vFLIP均介导IL-1Ra抑制。此外，GR信号在KSHV转化的细胞中被抑制，由vFLIP和vCyclin介导。地塞米松治疗激活了GR信号，并抑制KSHV转化细胞的软琼脂中的细胞增殖和集落形成，但对匹配的原代细胞影响最小。因此,地塞米松抑制小鼠KSHV诱导的肿瘤的发生和生长。机械上,地塞米松抑制IL-1α，但诱导IL-1Ra表达。用重组IL-1α蛋白处理挽救了地塞米松的抑制作用，而IL-1Ra的过表达对KSHV转化细胞的生长抑制作用较弱。此外，地塞米松诱导IκBα表达，导致NF-κB通路和IL-1α表达受到抑制。这些结果揭示了IL-1通路在KSHV诱导的炎症和肿瘤发生中的重要作用。可以被地塞米松激活的GR信号抑制，并确定IL-1介导的炎症是KSHV诱导的恶性肿瘤的潜在治疗靶标。
■卡波西肉瘤（KS）是由卡波西肉瘤相关疱疹病毒（KSHV）感染引起的HIV感染患者中最常见的癌症。炎症过度是KS的标志。在这项研究中,我们已经证明KSHV通过诱导IL-1α和抑制IL-1Ra介导炎症过度。机械上,KSHVmiRNA和vFLIP通过激活NF-κB途径诱导炎症过度。常见的抗炎药地塞米松通过激活糖皮质激素受体信号传导来抑制IL-1α并诱导IL-1Ra，从而阻断KSHV诱导的过度炎症和肿瘤发生。这项工作已经确定IL-1介导的炎症是潜在的治疗靶标，地塞米松是KSHV诱导的恶性肿瘤的潜在治疗剂。
■卡波西肉瘤（KS）是由卡波西肉瘤相关疱疹病毒（KSHV）感染引起的HIV感染患者中最常见的癌症。炎症过度是KS的标志。在这项研究中,我们已经证明KSHV通过诱导IL-1α和抑制IL-1Ra介导炎症过度。机械上,KSHVmiRNA和vFLIP通过激活NF-κB途径诱导炎症过度。常见的抗炎药地塞米松通过激活糖皮质激素受体信号传导来抑制IL-1α并诱导IL-1Ra，从而阻断KSHV诱导的过度炎症和肿瘤发生。这项工作已经确定IL-1介导的炎症是潜在的治疗靶标，地塞米松是KSHV诱导的恶性肿瘤的潜在治疗剂。
