HCMV-Encoded Chemokine Receptor US28 Mediates Proliferative Signaling Through the IL-6–STAT3 Axis

US28 is a viral G protein (heterotrimeric guanosine triphosphate - binding protein) - coupled receptor encoded by the human cytomegalovirus (HCMV). In addition to binding and internalizing chemokines, US28 constitutively activates signaling pathways linked to cell proliferation. Here, we show increased concentrations of vascular endothelial growth factor and interleukin-6 (IL-6) in supernatants of US28-expressing NIH 3T3 cells. Increased IL-6 was associated with increased activation of the signal transducer and activator of transcription 3 (STAT3) through upstream activation of the Janus-activated kinase JAK1. We used conditioned growth medium, IL-6-neutralizing antibodies, an inhibitor of the IL-6 receptor, and short hairpin RNA targeting IL-6 to show that US28 activates the IL-6-JAK1-STAT3 signaling axis through activation of the transcription factor nuclear factor κB and the consequent production of IL-6. Treatment of cells with a specific inhibitor of STAT3 inhibited US28-dependent [