Inhibition of NF-kappaB induces apoptosis of KSHV-infected primary effusion lymphoma cells.
Inhibition of NF-kappaB induces apoptosis of KSHV-infected primary effusion lymphoma cells.
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DOI：
10.1182/blood.v96.7.2537
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发表时间：
2000-10
期刊：
影响因子：
20.3
通讯作者：
S. Keller;E. Schattner;E. Cesarman
中科院分区：
文献类型：
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作者：
S. Keller;E. Schattner;E. Cesarman
卡波西肉瘤相关疱疹病毒(KSHV)或人类疱疹病毒8(HHV-8)是一种感染人类淋巴细胞的伽玛疱疹病毒，与原发性渗出性淋巴瘤(PEL)有关。目前，病毒感染在PEL细胞转化中的作用尚不清楚。一种可能性是，KSHV像嗜淋巴病毒(EBV)和人类T细胞白血病病毒I(HTLV-I)一样，激活转录因子NF-kappaB，促进受感染淋巴细胞的存活和增殖。为了验证这种可能性，我们用凝胶迁移率改变分析(EMSA)评估了KSHV感染的PEL细胞株和原发肿瘤标本中的核因子-kappaB活性。我们观察到，在所有KSHV感染的淋巴瘤中，NF-kappaB都被结构性地激活，并且由两个主要的复合体组成，即p65/p50异源二聚体和p50/p50同源二聚体。抑制实验表明，不可逆的IkappaBalpha磷酸化抑制剂Bay 11-7082可特异性地完全阻断PEL细胞中的核因子-kappaB/DNA结合。经BAY 11处理后，PEL细胞中核因子-kappaB诱导的细胞因子白介素6(IL-6)表达下调，细胞发生凋亡。这些结果表明，KSHV感染的淋巴瘤细胞生存所必需的是核因子-kappaB的活性，药物抑制核因子-kappaB可能是治疗PEL的有效方法。
Kaposi sarcoma-associated herpesvirus (KSHV), or human herpervirus 8 (HHV-8), is a gamma-herpesvirus that infects human lymphocytes and is associated with primary effusion lymphoma (PEL). Currently, the role of viral infection in the transformation of PEL cells is unknown. One possibility is that KSHV, like the lymphotropic viruses Epstein-Barr virus (EBV) and human T-cell leukemia virus I (HTLV-I), activates the transcription factor NF-kappaB to promote survival and proliferation of infected lymphocytes. To examine this possibility, we assessed NF-kappaB activity in KSHV-infected PEL cell lines and primary tumor specimens by electrophoretic mobility shift assay (EMSA). We observed that NF-kappaB is constitutively activated in all KSHV-infected lymphomas, and consists of 2 predominant complexes, p65/p50 heterodimers and p50/p50 homodimers. Inhibition experiments demonstrated that Bay 11-7082, an irreversible inhibitor of IkappaBalpha phosphorylation, completely and specifically abrogated the NF-kappaB/DNA binding in PEL cells. PEL cells treated with Bay 11 demonstrated down-regulation of the NF-kappaB inducible cytokine interleukin 6 (IL-6), and apoptosis. These results suggest that NF-kappaB activity is necessary for survival of KSHV-infected lymphoma cells, and that pharmacologic inhibition of NF-kappaB may be an effective treatment for PEL.