Activated expression of the chemokine Mig after chemotherapy contributes to chemotherapy-induced bone marrow suppression and lethal toxicity
Activated expression of the chemokine Mig after chemotherapy contributes to chemotherapy-induced bone marrow suppression and lethal toxicity
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DOI：
10.1182/blood-2011-07-367581
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发表时间：
2012-05-24
期刊：
影响因子：
20.3
通讯作者：
Moldenhauer, Anja
中科院分区：
文献类型：
--
作者：
Lu, Huili;Zhu, Shunying;Moldenhauer, Anja
化疗后基因表达的改变可能有助于识别诱导骨髓抑制或再生的介质。本文报告了我们的观察结果，即用化疗药物 5-氟尿嘧啶 (5-FU) 治疗后，小鼠体内由 IFN-γ (Mig) 及其受体 CXCR3 诱导的趋化因子单因子的表达显着激活。针对激活的 Mig 的抗体中和可提高化疗后的存活率并加速 BM 恢复。此外，5-FU 治疗后 Mig 血浆水平升高与死亡率增加相对应。在脾集落测定中，预防性施用 Mig 的细胞周期抑制作用可保护造血祖细胞 (HPC) 免受 1-β-D-阿拉伯呋喃糖基胞嘧啶的影响，并增强受辐射受体的存活率。在CXCR3(-/-)小鼠中，Mig没有传播BM抑制，表明Mig的抑制作用依赖于CXCR3。一方面，Mig 刺激间充质基质细胞中的 p70 S6K 和 Erk1/2 通路，抑制间充质基质细胞依赖性 HPC 扩增。此外，Mig 抑制 HPC 中的 STAT5 通路，抑制白细胞分化。我们的结果强烈表明，Mig 会导致 5-FU 给药引起的急性致死毒性。 Mig 的中和可能提供减轻 BM 毒性的新策略，对化疗具有潜在的巨大影响。 （血。2012；119(21):4868-4877）
Alterations in gene expression after chemotherapy may potentially help to identify mediators that induce suppression or regeneration in bone marrow. This paper reports our observation that the expression of the chemokine monokine induced by IFN-gamma (Mig) and its receptor CXCR3 was significantly activated in mice after treatment with the chemotherapeutic agent 5-fluorouracil (5-FU). The neutralization of antibodies against the activated Mig increased the survival rate and accelerated BM recovery after chemotherapy. In addition, elevation of Mig plasma levels after 5-FU treatment corresponded with increased mortality. The cell cycle-inhibiting effect of the prophylactic administration of Mig protected hematopoietic progenitor cells (HPCs) from 1-beta-D-arabinofuranosylcytosine in spleen colony assays and enhanced the irradiated recipients' survival. In CXCR3(-/-) mice, Mig did not propagate BM suppression, indicating that the suppressive effect of Mig is dependent on CXCR3. On the one hand, Mig stimulated p70 S6K and Erk1/2 pathways in mesenchymal stroma cells, inhibiting mesenchymal stroma cell-dependent HPC expansion. Moreover, Mig suppressed the STAT5 pathway in HPCs, inhibiting leukocyte differentiation. Our results strongly suggest that Mig contributes to the acute lethal toxicity arising from 5-FU administration. Neutralization of Mig may offer new strategies to alleviate BM toxicity with potentially dramatic implications for chemotherapy. (Blood. 2012;119(21):4868-4877)