Angiogenesis and hematopoiesis induced by Kaposi's sarcoma-associated herpesvirus-encoded interleukin-6

Kaposi's sarcoma-associated herpesvirus (KSHV; also known as human herpesvi rus 8 [HHV-8]) is a herpesvirus linked to the development of Kaposi's sarco ma (KS), primary effusion lymphoma, and a proportion of Castleman's disease . KSHV encodes viral interleukin-6 (vIL-6), which is structurally homologou s 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 m urine fibroblasts NIH3T3 cells and inoculated stable vIL-6-producing clones into athymic mice. vIL-6 was detected selectively in the blood of mice inj ected with vIL-6-expressing clones. Compared with controls, vIL-6-positive mice displayed increased hematopoiesis in the myeloid, erythroid, and megak aryocytic lineages; plasmacytosis in spleen and lymph nodes; hepatosplenome galy; 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 f actor (VEGF) was detected at higher levels in the culture supernatant of vI L-6-expressing cells compared with controls, and immunohistochemical staini ng detected VEGF in spleen, lymph nodes, and tumor tissues from mice bearin g vIL-6-producing tumors but not control tumors. Thus, vIL-6 is a multifunc tional cytokine that promotes hematopoiesis, plasmacytosis, and angiogenesi s, Through these functions, vIL-6 may play an important role in the pathoge nesis of certain KSHV-associated disorders. (C) 1999 by The American Societ y of Hematology.