Kaposis Sarcoma Associated Herpsvirus KSHV in malignancy

Kapsis肉瘤相关疱疹病毒(KSHV)与Kapsis肉瘤、原发性渗出性淋巴瘤(PEL)和部分卡斯特尔曼病的发生有关。KSHV编码几种细胞因子和趋化素样蛋白，包括白介素6(IL-6)的同源物。病毒(V)IL-6主要在病毒复制过程中产生，与人和小鼠IL-6有大约25%的氨基酸同源性，提示它可能是病毒盗用有用的细胞基因的结果。通过体内外实验，我们对VIL-6的生物学活性进行了表征。用VIL-6治疗的小鼠表现出髓系、红系和巨核系的造血量增加，脾和淋巴结的浆细胞增多，肝脾肿大和多克隆性高丙种球蛋白血症。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刺激血管内皮细胞生长因子(VEGF)的表达。在其他实验中，我们探讨了血管内皮生长因子在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的淋巴瘤，并且表达VIL-6和血管内皮生长因子，我们研究了血管内皮生长因子是否可能是发生PEL积液所必需的。利用实验性PEL小鼠模型，我们发现抗人血管内皮生长因子的中和抗体阻止了SCID/Beige小鼠实验性PEL的发展。因此，我们认为VIL-6和VIL-6诱导的血管内皮细胞生长因子可能在某些KSHV相关疾病的发病机制中起关键作用。

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.