Department of Biology, Indiana University-Purdue University Indianapolis School of Science, Indianapolis, IN 46202, USA.
Blood. 2011 Dec 1;118(23):6097-106. doi: 10.1182/blood-2011-03-341867. Epub 2011 Oct 13.
Signal Transducer and Activator of Transcription 4 (STAT4) is a transcription factor that is activated by IL-12 signaling and promotes Th1-cell differentiation and IFN-γ production. Defective IFN-γ production because of STAT4 mRNA and protein deficiency occurs after autologous stem cell transplantation for lymphoma. In the present study, we investigated the mechanisms of STAT4 deficiency in lymphoma patients. The tumor-bearing state is not responsible, because STAT4 levels were not significantly different in PBMCs obtained from healthy control subjects compared with those from lymphoma patients before treatment. STAT4 protein levels were significantly decreased in PBMCs and T cells obtained from lymphoma patients after standard-dose chemotherapy. Furthermore, treatment of control PBMC cultures or a natural killer cell line with chemotherapy drugs in vitro also resulted in reduced STAT4 protein and diminished, IL-12-induced IFN-γ production. Translation of STAT4 protein was not impaired in chemotherapy-treated cells, whereas the STAT4 protein half-life was significantly reduced. Chemotherapy drugs promoted the ubiquitination and proteasomal degradation of STAT4. Treatment with the proteasome inhibitor bortezomib reversed chemotherapy-induced STAT4 deficiency and defective IFN-γ production. We conclude that acquired STAT4 deficiency in lymphoma patients is a consequence of treatment with chemotherapy, results that have important implications for the design of optimal immunotherapy for lymphoma.
信号转导子和转录激活子 4（STAT4）是一种转录因子，可被 IL-12 信号激活，促进 Th1 细胞分化和 IFN-γ 产生。由于自体干细胞移植治疗淋巴瘤后 STAT4 mRNA 和蛋白缺陷，导致 IFN-γ 产生受损。在本研究中，我们研究了淋巴瘤患者 STAT4 缺陷的机制。肿瘤负荷状态不是造成 STAT4 缺陷的原因，因为与治疗前的淋巴瘤患者相比，健康对照者外周血单个核细胞（PBMCs）中 STAT4 水平没有显著差异。标准剂量化疗后，从淋巴瘤患者 PBMCs 和 T 细胞中提取的 STAT4 蛋白水平显著降低。此外，体外用化疗药物处理对照 PBMC 培养物或自然杀伤细胞系也导致 STAT4 蛋白减少，IL-12 诱导的 IFN-γ 产生减少。化疗处理细胞中 STAT4 蛋白的翻译没有受损，而 STAT4 蛋白半衰期明显缩短。化疗药物促进 STAT4 的泛素化和蛋白酶体降解。用蛋白酶体抑制剂硼替佐米治疗可逆转化疗诱导的 STAT4 缺陷和 IFN-γ 产生缺陷。我们得出结论，淋巴瘤患者获得性 STAT4 缺陷是化疗治疗的结果，这对设计淋巴瘤最佳免疫治疗具有重要意义。
