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 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 signaling axis through activation of the transcription factor nuclear factor kappaB and the consequent production of IL-6. Treatment of cells with a specific inhibitor of inhibited US28-dependent [(3)H]thymidine incorporation and foci formation, suggesting a key role for duanyu18133 in the US28-mediated proliferative phenotype. US28 also elicited duanyu18133 activation and IL-6 secretion in HCMV-infected cells. Analyses of tumor specimens from glioblastoma patients demonstrated colocalization of US28 and phosphorylated duanyu18133 in the vascular niche of these tumors. Moreover, increased abundance correlated with poor patient outcome. We propose that US28 induces proliferation in HCMV-infected tumors by establishing a positive feedback loop through activation of the signaling axis.

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