Kaposis Sarcoma Associated Herpsvirus KSHV in malignancy

卡波西肉瘤相关疱疹病毒（KSHV）与卡波西肉瘤、原发性渗出性淋巴瘤（PEL）和部分Castleman病的发生有关。 KSHV编码几种细胞因子和趋化因子样蛋白，包括白细胞介素-6（IL-6）的同源物。 主要在病毒复制期间产生的病毒（v）IL-6与人和鼠IL-6具有约25%的氨基酸同一性，表明其可能是有用的细胞基因的病毒盗版的结果。通过体外和体内实验，我们对vIL-6的生物学活性进行了表征。 用vIL-6处理的小鼠在骨髓、红细胞和巨核细胞谱系中表现出造血增加;脾和淋巴结中的浆细胞增多;肝脾肿大;和多克隆高丙种球蛋白血症。 我们确定表达vIL-6的成纤维细胞比对照细胞更快地产生肿瘤，并确定vIL-6刺激血管内皮生长因子（VEGF）的表达。 在另外的实验中，我们探讨了VEGF在PEL发病机制中的潜在作用。 由于PEL是一种主要以液体形式生长并表达vIL-6和VEGF的淋巴瘤，我们研究了VEGF是否可能是PEL积液发展所必需的。 使用实验性小鼠模型的PEL发展，我们发现，中和抗体对人VEGF阻止SCID/米色小鼠实验性PEL的发展。 因此，我们已经表明，vIL-6和VEGF诱导的vIL-6可能是关键的某些KSHV相关疾病的发病机制。

Kaposis sarcoma associated herpesvirus (KSHV) has been linked to the development of Kaposis sarcoma, primary effusion lymphoma (PEL) and a proportion of Castlemans disease. KSHV encodes several cytokine- and chemokine-like proteins, including a homologue of interleukin-6 (IL-6). Viral (v) IL-6, produced predominantly during viral replication, exibits approximately 25% amino acid identity to human and murine IL-6, suggesting that it may be the result of viral piracy of a useful cellular gene. Through experiments in vitro and in vivo, we have characterized the biological activities of vIL-6. Mice treated with vIL-6 displayed increased hematopoiesis in the myeloid, erythroid, and megakaryocytic lineages; plasmacytosis in spleen and lymph nodes; hepatosplenomegaly; and polyclonal hypergammaglobulinemia. We determined that vIL-6 expressing fibroblasts gave rise to tumors more rapidly than did control cells, and determined that vIL-6 stimulated vascular endothelial growth factor (VEGF) expression. In additional experiments, we explored the potential role of VEGF in PEL pathogenesis. Since PEL is a lymphoma that grows predominantly in liquid form and expresses vIL-6 and VEGF, we examined whether VEGF may be required for the development of PEL effusions. Using an experimental murine model of PEL development, we found that neutralizing antibodies against human VEGF prevented the development of experimental PEL in SCID/beige mice. Thus, we have shown that vIL-6 and VEGF induced by vIL-6 may be critical to the pathogenesis of certain KSHV-associated diseases.