Angiogenesis and hematopoiesis induced by Kaposi's sarcoma-associated herpesvirus-encoded interleukin-6.
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.
Aoki
Y
Y
Division of Hematologic Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD, USA. AOKI@CBER.FDA.GOV
Jaffe
E S
ES
Chang
Y
Y
Jones
K
K
Teruya-Feldstein
J
J
Moore
P S
PS
Tosato
G
G
D016475:3T3 Cells; D000818:Animals; D016228:Endothelial Growth Factors / Q000032:analysis; D004920:Erythropoiesis; D006098:Granulocytes; D006410:Hematopoiesis; D006529:Hepatomegaly; D019288:Herpesvirus 8, Human / Q000235:genetics*; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000494:pharmacology*; D008198:Lymph Nodes / Q000473:pathology; D008222:Lymphokines / Q000032:analysis; D008533:Megakaryocytes; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000821:virology*; D010950:Plasma Cells / Q000473:pathology; D011994:Recombinant Proteins / Q000494:pharmacology; D013154:Spleen / Q000473:pathology; D013163:Splenomegaly; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D015850:Interleukin-6; D008222:Lymphokines; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors