Kaposis Sarcoma Associated Herpsvirus KSHV in malignancy

Kaposis sarcoma associated herpesvirus （KSHV）与Kaposis sarcoma、原发性积液性淋巴瘤（PEL）和一部分Castlemans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。病毒(v) IL-6主要在病毒复制过程中产生，与人类和小鼠IL-6具有约25%的氨基酸同源性，这表明它可能是病毒窃取有用细胞基因的结果。通过体外和体内实验，我们对vIL-6的生物活性进行了表征。用vIL-6处理的小鼠显示髓系、红系和巨核细胞系的造血能力增加；脾脏及淋巴结浆细胞增多症；肝脾肿大;以及多克隆性高γ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。在其他实验中，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il -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PEL发展模型，我们发现抗人VEGF的中和抗体阻止了SCID/beige小鼠实验性PEL的发展。因此，我们已经表明，vIL-6和由vIL-6诱导的VEGF可能对某些kshv相关疾病的发病机制至关重要。

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.