PDF(Pubmed)
Abstract：
Following infection or exposure to therapeutic agents, an aggressive immune response may result, termed cytokine storm (CS) or cytokine release syndrome. Here the innate immune system becomes uncontrolled, leading to serious consequences including possible death. Patients surviving CS are at greater risk for de novo tumorigenesis, but it is unclear if any specific cytokines are directly responsible for this outcome. De novo tumorigenesis has been observed in donated cells exposed to CS following haematopoietic stem cell transplant (HSCT). Modelling HSCT, we firstly demonstrated the release of CS levels from the HS-5 human bone marrow stromal cell line, post-exposure to chemotherapy. We then exposed the TK6 lymphoblast cell line to healthy and storm doses of IL-6 and measured increased genotoxicity via the micronucleus assay. During HSCT, haematopoietic cells are exposed to a complex mix of cytokines, so to determine if IL-6 was integral in a chemotherapy-induced bystander effect, we attempted to inhibit IL-6 from HS-5 cells using resatorvid or siRNA, treated with chlorambucil or mitoxantrone, and then co-cultured with bystander TK6 cells. Whilst resatorvid did not reduce IL-6 and did not reduce micronuclei in the bystander TK6 cells, siRNA inhibition reduced IL-6 to healthy in vivo levels, and micronuclei aligned with untreated controls. Our data suggests that exposure to high IL-6 (in the absence of inflammatory cells) has potential to induce genetic damage and may contribute to de novo tumorigenesis post-CS. We suggest that for individuals with a pro-inflammatory profile, anti-IL-6 therapy may be an appropriate intervention to prevent complications post-CS.
摘要：
感染或接触治疗剂后，可能会导致侵袭性的免疫反应，称为细胞因子风暴（CS）或细胞因子释放综合征。这里的先天免疫系统变得不受控制，导致严重的后果，包括可能的死亡。CS存活的患者有更大的从头肿瘤发生的风险，但目前尚不清楚是否有任何特定的细胞因子直接导致这一结果.在造血干细胞移植（HSCT）后暴露于CS的捐赠细胞中观察到了从头肿瘤发生。HSCT建模，我们首先证明了HS-5人骨髓基质细胞系中CS水平的释放，暴露于化疗后。然后，我们将TK6淋巴母细胞细胞系暴露于健康和风暴剂量的IL-6，并通过微核试验测量了增加的遗传毒性。在HSCT期间，造血细胞暴露于复杂的细胞因子混合物，因此，为了确定IL-6是否在化疗诱导的旁观者效应中不可或缺，我们尝试使用resatorvid或siRNA抑制HS-5细胞中的IL-6，用苯丁酸氮芥或米托蒽醌处理，然后与旁观者TK6细胞共培养。虽然resatorvid没有减少IL-6，也没有减少旁观者TK6细胞中的微核，siRNA抑制将IL-6降低至健康体内水平，和微核与未处理的对照对齐。我们的数据表明，暴露于高IL-6（在没有炎症细胞的情况下）有可能诱导遗传损伤，并可能导致CS后的从头肿瘤发生。我们建议，对于具有促炎性质的个体，抗IL-6治疗可能是预防CS后并发症的适当干预措施。
