Human herpesvirus 8 (HHV-8)-encoded cytokines induce expression of and autocrine signaling by vascular endothelial growth factor (VEGF) in HHV-8-infected primary-effusion lymphoma cell lines and mediate VEGF-independent antiapoptotic effects.
The potential roles of human herpesvirus 8 (HHV-8) cytokines in HHV-8 pathogenesis were investigated by determining the expression of the HHV-8 chemokines viral macrophage inflammatory protein 1A (vMIP-1A) and vMIP-1B in primary effusion lymphoma (PEL)-derived cell lines and examining the signaling activities of these chemokines and HHV-8-encoded vIL-6 in these cells. Secreted vMIP-1A and vMIP-1B were detected in biologically significant concentrations following tetradecanoyl phorbol acetate treatment, which induces productive replication. vIL-6 and vMIP-1A, added exogenously to cultures of four different PEL cell lines, induced the expression of vascular endothelial growth factor type B (VEGF-B) and VEGF-A, respectively. These cells were found to express VEGF receptor 1 (Flt-1) protein, and signaling by recombinant VEGF-A(165) was demonstrated for two of the PEL cell lines, indicating the potential for autocrine, as well as paracrine, effects of viral cytokine-induced VEGF. In addition, vMIP-1A and vMIP-1B, but not VEGF-A(165), were found to inhibit chemically induced apoptosis in PEL cells. Our data suggest that vIL-6 and vMIP-1A may influence PEL through VEGF autocrine and paracrine signaling that promotes PEL cell growth and extravascular effusion and that vMIP-1A and vMIP-1B can act independently of VEGF as antiapoptotic factors.
Liu
C
C
Molecular Virology Laboratories, Johns Hopkins Oncology Center, Baltimore, Maryland 21231, USA.
Okruzhnov
Y
Y
Li
H
H
Nicholas
J
J
D000818:Animals; D017209:Apoptosis; D054407:Chemokine CCL4; D016207:Cytokines / Q000502:physiology*; D016228:Endothelial Growth Factors / Q000502:physiology*; D019288:Herpesvirus 8, Human / Q000502:physiology*; D006801:Humans; D015850:Interleukin-6 / Q000502:physiology; D008222:Lymphokines / Q000502:physiology*; D008223:Lymphoma / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D019402:Macrophage Inflammatory Proteins / Q000502:physiology; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis; D017978:Receptors, Growth Factor / Q000096:biosynthesis; D040262:Receptors, Vascular Endothelial Growth Factor; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D054407:Chemokine CCL4; D016207:Cytokines; D016228:Endothelial Growth Factors; D015850:Interleukin-6; D008222:Lymphokines; D019402:Macrophage Inflammatory Proteins; D017978:Receptors, Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor