Angiogenesis and Hematopoiesis Induced by Kaposi’s Sarcoma-Associated Herpesvirus-Encoded Interleukin-6

Abstract

Abstract Kaposi’s sarcoma-associated herpesvirus (KSHV; also known as human herpesvirus 8 [HHV-8]) is a herpesvirus linked to the development of Kaposi’s sarcoma (KS), primary effusion lymphoma, and a proportion of Castleman’s disease. KSHV encodes viral interleukin-6 (vIL-6), which is structurally homologous to human and murine IL-6. The biological activities of vIL-6 are largely unknown. To gain insight into the biology of vIL-6, we expressed vIL-6 in murine fibroblasts NIH3T3 cells and inoculated stable vIL-6–producing clones into athymic mice. vIL-6 was detected selectively in the blood of mice injected with vIL-6–expressing clones. Compared with controls, vIL-6–positive mice displayed increased hematopoiesis in the myeloid, erythroid, and megakaryocytic lineages; plasmacytosis in spleen and lymph nodes; hepatosplenomegaly; and polyclonal hypergammaglobulinemia. vIL-6–expressing NIH3T3 cells gave rise to tumors more rapidly than did control cells, and vIL-6–positive tumors were more vascularized than controls. Vascular endothelial growth factor (VEGF) was detected at higher levels in the culture supernatant of vIL-6–expressing cells compared with controls, and immunohistochemical staining detected VEGF in spleen, lymph nodes, and tumor tissues from mice bearing vIL-6–producing tumors but not control tumors. Thus, vIL-6 is a multifunctional cytokine that promotes hematopoiesis, plasmacytosis, and angiogenesis. Through these functions, vIL-6 may play an important role in the pathogenesis of certain KSHV-associated disorders.