Kaposi's sarcoma-associated herpesvirus-G protein-coupled receptor-expressing endothelial cells exhibit reduced migration and stimulated chemotaxis by chemokine inverse agonists.
A constitutively active G protein-coupled receptor (GPCR) encoded by Kaposi's sarcoma-associated herpesvirus (human herpesvirus-8) (KSHV) is expressed in endothelial (spindle) cells of Kaposi's sarcoma lesions. In this study, we report novel effects of basal signaling by this receptor and of inverse agonist chemokines on migration of KSHV-GPCR-expressing mouse lung endothelial cells. We show that basal signaling by KSHV-GPCR inhibits migration of endothelial cells in two systems, movement through porous filters and in vitro wound closure. Naturally occurring chemokines, interferon gamma-inducible protein-10 and stromal-derived factor-1, which act as inverse agonists at KSHV-GPCR, abrogate the inhibition of migration and stimulate directed migration (or chemotaxis) of these cells. Thus, the expression of KSHV-GPCR may allow infected endothelial cells in situ to remain in a localized environment or to directionally migrate along a gradient of specific chemokines that are inverse agonists at KSHV-GPCR.
Couty
Jean-Pierre
JP
Clinical Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Lupu-Meiri
Monica
M
Oron
Yoram
Y
Gershengorn
Marvin C
MC
D000818:Animals; D002460:Cell Line; D054360:Chemokine CXCL1 / Q000494:pharmacology; D054357:Chemokine CXCL10 / Q000494:pharmacology; D054371:Chemokine CXCL11 / Q000494:pharmacology; D054377:Chemokine CXCL12 / Q000494:pharmacology; D054370:Chemokine CXCL9 / Q000494:pharmacology; D018925:Chemokines / Q000494:pharmacology*; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology*; D054314:Drug Inverse Agonism; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019707:Receptors, Chemokine / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014162:Transfection; D014945:Wound Healing / Q000187:drug effects; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
D054360:Chemokine CXCL1; D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D054377:Chemokine CXCL12; D054370:Chemokine CXCL9; D018925:Chemokines; C115448:G protein-coupled receptor, Human herpesvirus 8; D019707:Receptors, Chemokine; D011505:Protein-Tyrosine Kinases; D051059:PTEN Phosphohydrolase; D020741:rho GTP-Binding Proteins