Inhibition of Inflammatory Interleukin-6 Activity via Extracellular Signal-Regulated Kinase–Mitogen-Activated Protein Kinase Signaling Antagonizes Human Cytomegalovirus Reactivation from Dendritic Cells
- 1 December 2011
- journal article
- Published by American Society for Microbiology in Journal of Virology
- Vol. 85 (23), 12750-12758
- https://doi.org/10.1128/jvi.05878-11
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.Keywords
This publication has 44 references indexed in Scilit:
- Experimental human cytomegalovirus latency in CD14+monocytesProceedings of the National Academy of Sciences, 2010
- Cytomegalovirus Reactivation in Critically Ill Immunocompetent PatientsJAMA, 2008
- Human Cytomegalovirus Secretome Contains Factors That Induce Angiogenesis and Wound HealingJournal of Virology, 2008
- Analyzing real-time PCR data by the comparative CT methodNature Protocols, 2008
- Improving Outcomes for Solid-Organ Transplant Recipients At Risk from Cytomegalovirus Infection: Late-Onset Disease and Indirect ConsequencesClinical Infectious Diseases, 2008
- Activin-A: a novel dendritic cell–derived cytokine that potently attenuates CD40 ligand–specific cytokine and chemokine productionBlood, 2008
- Human cytomegalovirus sequences expressed in latently infected individuals promote a latent infection in vitroBlood, 2007
- Reversal of Human Cytomegalovirus Major Immediate-Early Enhancer/Promoter Silencing in Quiescently Infected Cells via the Cyclic AMP Signaling PathwayJournal of Virology, 2007
- Recognition of cytomegalovirus clinical isolate antigens by sera from cytomegalovirus-negative blood donorsTransfusion, 2004
- Susceptibility of Immature and Mature Langerhans Cell-Type Dendritic Cells to Infection and Immunomodulation by Human CytomegalovirusJournal of Virology, 2003