title: Inhibition of inflammatory interleukin-6 activity via extracellular signal-regulated kinase-mitogen-activated protein kinase signaling antagonizes human cytomegalovirus reactivation from dendritic cells.
abstract: Human cytomegalovirus (HCMV) remains a major cause of viral disease in immunosuppressed transplant patients. The ability of HCMV to establish lifelong infection in humans and reactivate with devastating clinical consequences underscores the importance of understanding the triggers of HCMV reactivation in mature myeloid cells. Dendritic cell (DC) differentiation is concomitant with the activation of cellular signaling pathways and inflammatory gene expression and also HCMV reactivation. Here, we show a major role for interleukin-6 (IL-6) through extracellular signal-regulated kinase-mitogen-activated protein kinase (ERK-MAPK) signaling upon DC differentiation to promote HCMV reactivation. IL-6 drives reactivation by transcriptional upregulation of the major immediate-early (IE) genes, resulting in efficient progression of the virus life cycle and, ultimately, higher titers of infectious virus. Furthermore, the interception of IL-6 signaling with biological inhibitors significantly abrogated HCMV reactivation from experimental latency. Crucially, using cells derived from healthy seropositive donors, we observed a key role for IL-6 during reactivation from natural latency ex vivo in interstitial DCs. Clinically, HCMV reactivation occurs in highly inflammatory environments (i.e., transplantation); thus, the implications of this study could potentially provide novel approaches for therapeutic intervention.
authors.affiliation: Department of Infectious Diseases, Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Reeves
authors.forename: Teresa
authors.initials: T
authors.lastname: Compton
mesh_terms: D015153:Blotting, Western; D002454:Cell Differentiation; D002478:Cells, Cultured; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections / Q000235:genetics / Q000378:metabolism / Q000821:virology*; D003713:Dendritic Cells / Q000378:metabolism / Q000821:virology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D015967:Gene Expression Regulation, Viral; D017781:Genes, Immediate-Early; D006801:Humans; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors*; D015850:Interleukin-6 / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology / Q000378:metabolism / Q000821:virology; D022423:Myeloid Cells / Q000166:cytology / Q000378:metabolism / Q000821:virology; D012333:RNA, Messenger / Q000235:genetics; D055213:Retinal Pigment Epithelium / Q000166:cytology / Q000378:metabolism / Q000821:virology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D015533:Transcriptional Activation; D014775:Virus Activation / Q000502:physiology*; D017735:Virus Latency; D000093242:Interleukin-6 Inhibitors
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases; D018836:Inflammation Mediators; D015850:Interleukin-6; D020928:Mitogen-Activated Protein Kinases; D012333:RNA, Messenger; D000093242:Interleukin-6 Inhibitors