Triggering of DC migration by dengue virus stimulation of COX-2-dependent signaling cascades in vitro highlights the significance of these cascades beyond inflammation.
A term "bone-breaking fever" is used in Chinese medicine to describe the symptoms of patients infected with dengue virus (DV). We examined the significance of the COX-prostaglandin pathway in human DC infected by DV. We show that DV infection induced the expression of COX-2 and the production of prostaglandin E2 (PGE2) in DC, and stimulated the DNA binding of NF-kappaB and the kinase activity of both IkappaBalpha kinase (IKK) alpha and beta. DV infection also activated MAPK and AP-1 signaling. Both IkappaBalpha kinase-NF-kappaB and MAPK-AP-1 were upstream of COX-2 activation. Our investigation into the significance of COX-2-PGE2 pathway also revealed that DV infection enhances DC migration by inducing CC chemokine receptor 7 (CCR7) expression, and that blocking COX-2 or MAPK activity suppresses DV-induced DC migration. Our data also suggest that PGE2 can induce CCR7 expression on DC and that antagonists of the PGE2 receptors EP2 and EP4 suppress DV-induced DC migration. We further show that the increased CCR7 expression was observed in both DV-infected and bystander DC, suggesting the presence of secondary effects in inducing CCR7 expression. Collectively, this study reveals not only the pathways involved in COX-2 synthesis in DV-infected DC but also the autocrine action of PGE2 on the migration of DV-infected DC.
Wu
Wan-Lin
WL
Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
Ho
Ling-Jun
LJ
Chang
Deh-Ming
DM
Chen
Chen-Hung
CH
Lai
Jenn-Haung
JH
D015153:Blotting, Western; D002465:Cell Movement; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D003713:Dendritic Cells / Q000166:cytology / Q000378:metabolism / Q000821:virology*; D003716:Dengue Virus / Q000502:physiology*; D015232:Dinoprostone / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D054884:Host-Pathogen Interactions; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D054400:Receptors, CCR7 / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000378:metabolism; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C515370:CCR7 protein, human; D016328:NF-kappa B; C545644:PTGER2 protein, human; C545650:PTGER4 protein, human; D054400:Receptors, CCR7; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D018808:Transcription Factor AP-1; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D015232:Dinoprostone