Activation of NF-kappaB by the human herpesvirus 8 chemokine receptor ORF74: evidence for a paracrine model of Kaposi's sarcoma pathogenesis.
Infection with human herpesvirus 8 (HHV-8), also known as Kaposi's sarcoma (KS)-associated herpesvirus, is necessary for the development of KS. The HHV-8 lytic-phase gene ORF74 is related to G protein-coupled receptors, particularly interleukin-8 (IL-8) receptors. ORF74 activates the inositol phosphate/phospholipase C pathway and the downstream mitogen-activated protein kinases, JNK/SAPK and p38. We show here that ORF74 also activates NF-kappaB independent of ligand when expressed in KS-derived HHV-8-negative endothelial cells or primary vascular endothelial cells. NF-kappaB activation was enhanced by the chemokine GROalpha, but not by IL-8. Mutation of Val to Asp in the ORF74 second cytoplasmic loop did not affect ligand-independent signaling activity, but it greatly increased the response to GROalpha. ORF74 upregulated the expression of NF-kappaB-dependent inflammatory cytokines (RANTES, IL-6, IL-8, and granulocyte-macrophage colony-stimulating factor) and adhesion molecules (VCAM-1, ICAM-1, and E-selectin). Supernatants from transfected KS cells activated NF-kappaB signaling in untransfected cells and elicited the chemotaxis of monocytoid and T-lymphoid cells. Expression of ORF74 conferred on primary endothelial cells a morphology that was strikingly similar to that of spindle cells present in KS lesions. Taken together, these data, demonstrating that ORF74 activates NF-kappaB and induces the expression of proangiogenic and proinflammatory factors, suggest that expression of ORF74 in a minority of cells in KS lesions could influence uninfected cells or latently infected cells via autocrine and paracrine mechanisms, thereby contributing to KS pathogenesis.
Pati
S
S
Institute of Human Virology, University of Maryland Biotechnology Institute, Baltimore, Maryland 21201, USA.
Cavrois
M
M
Guo
H G
HG
Foulke
J S
JS
Kim
J
J
Feldman
R A
RA
Reitz
M
M
D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000096:biosynthesis; D002634:Chemotaxis, Leukocyte / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism; D019040:E-Selectin / Q000096:biosynthesis; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis; D019288:Herpesvirus 8, Human / Q000378:metabolism*; D006801:Humans; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D008954:Models, Biological; D009000:Monocytes / Q000502:physiology; D016296:Mutagenesis; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D019899:Paracrine Communication; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism*; D012514:Sarcoma, Kaposi; D013601:T-Lymphocytes / Q000502:physiology; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases
D018946:Chemokine CCL5; D004268:DNA-Binding Proteins; D019040:E-Selectin; D020672:I-kappa B Proteins; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C105181:ORF74 protein, Human herpesvirus 8; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D019707:Receptors, Chemokine; D019010:Vascular Cell Adhesion Molecule-1; D014764:Viral Proteins; D018799:Intercellular Adhesion Molecule-1; D000072000:NF-KappaB Inhibitor alpha; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases