Triggering of DC migration by dengue virus stimulation of COX‐2‐dependent signaling cascades in vitro highlights the significance of these cascades beyond inflammation

Abstract

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 COXprostaglandin pathway in human DC infected by DV. We show that DV infection induced the expression of COX-2 and the production of prostaglandin E 2 (PGE 2 ) in DC, and stimulated the DNA binding of NF-jB and the kinase activity of both IjBa kinase (IKK) a and b. DV infection also activated MAPK and AP-1 signaling. Both IjBa kinase-NF-jB and MAPK-AP-1 were upstream of COX-2 activation. Our investigation into the significance of COX-2-PGE 2 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 PGE 2 can induce CCR7 expression on DC and that antagonists of the PGE 2 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 PGE 2 on the migration of DV-infected DC.Key words: COX-2 . DC . Dengue virus . Inflammation Supporting Information available online IntroductionDengue viruses (DV) are members of the mosquito-borne flaviviruses that infect humans and cause dengue fever with potential severe outcomes such as dengue hemorrhagic fever and dengue shock syndrome [1,2]. DV infection occurs in most tropical and subtropical areas of the world and has become one of the major concerns for those traveling to these areas [3]. Epidemiological analysis reveals that worldwide the estimated occurrence is around 50-100 million cases for dengue fever yearly and for dengue hemorrhagic fever is about 250-500 thousand cases [4]. Efforts aiming to developing a vaccine have not yet been successful [5]. This may be due to the complicated mechanisms of immunopathogenesis [6,7]. Interestingly, Eur. J. Immunol. 2009. 39: 3413-3422 DOI 10.1002 Immunomodulation 3413 although the members of flaviviruses vary, a recent observation by Moran et al. [8] shows that a subset of residues within an epitope bound to a class II molecule are cross-reactively recognized by CD4 1 TCR.The term ''bone-breaking fever'' has long been used in Chinese medicine to describe the symptoms of DV-infected patients. Accordingly, the activation of COX-2-related signaling pathways may be involved in the pathogenesis of DV infection and thus contributes to the clinical manifestations. One of the products of this pathway, prostaglandin E 2 (PGE 2 ), has been shown to modulate inflammatory reactions [9] and regulate viral replication [10]. Given the important roles of COX-2-PGE 2 in many inflammatory responses on different host cells, it is surprising that the induction of COX-2-PGE 2 has not been consistently observed in experimental vira...

The Cytokine Response of U937-Derived Macrophages Infected through Antibody-Dependent Enhancement of Dengue Virus Disrupts Cell Apical-Junction Complexes and Increases Vascular Permeability

“…The "cytokine storm" described years ago as the excessive release of proinflammatory cytokines in several infectious diseases has been associated to SD (38). This phenomenon is supported by several clinical and in vitro studies in which increased concentrations of TNF-␣, IL-6, IL-1␤, IL-8, IL-12p70, IL-10, and PGE2 were connected to hemorrhage and to the immune response observed in human peripheral blood mononuclear cells (PBMCs) obtained from patients with SD (39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49). Our data suggest a cytokine secretion profiles that is more specific than a "storm" in macrophages infected under ADE conditions that may play a leading role in the pathogenesis of VPS by inducing a bias toward a T-helper-2 response (50).…”

Cyclooxygenase-2-prostaglandin E2-eicosanoid receptor inflammatory axis: a key player in Kaposi's sarcoma-associated herpes virus associated malignancies

“…Infections by several viruses have been shown to regulate COX-2 expression and PGE2 production such as HBV in hepatocytes, 28,29 HCV in Huh-7 cells, 30 human herpesvirus 6 (HHV-6) in monocytes, 31 human cytomegalovirus (CMV) in Peripheral blood mononuclear cells (PBMCs), smooth muscle cells, and fibroblasts, [32][33][34][35] murine gammaherpesvirus 68 (MHV-68) in NIH 3T3 cells, 36 HIV in monocytes, 37,38 HTLV-1 in PBMCs, 39 influenza virus in PBMCs, 40 enterovirus 71 in human neuroblastoma cells, 41 dengue virus in dendritic cells, 42 Severe acute respiratory syndrome (SARS)-associated coronavirus in 293T cells, 43 Theiler's murine encephalomyelitis virus in astrocytes, 44 encephalomyocarditis virus in macrophages, 45,46 coxsackie virus B3 in monocytes, 47 respiratory syncytial virus in macrophages and dendritic cells, 48 and canine distemper virus in monocytes. 49 COX-2/PGE2 has been implicated in a multitude of viral mechanisms such as genome replication (HBV), (CMV, HTLV), gene expression (MHV-68), transmission (HTLV), cell tropism (rhesus CMV), cell invasion (CMV), T cell regulation (HIV), and even has identified a viral homologue of COX-2 in rhesus CMV revealing the significance of COX-2 in the evolution of inflammation mediated viral pathogenesis.…”

Cyclooxygenase‐2 facilitates dengue virus replication and serves as a potential target for developing antiviral agents

“…Several reports have shown that the suppression of COX-2 expression and PGE 2 production by selective COX-2 inhibitors or non-steroidal anti-inflammatory drugs (NSAIDs) has an antiviral effect, attenuating disease severity in, for example, herpes simplex virus (HSV)14, influenza H5N115, Japanese encephalitis virus (JEV)16, EV7117, and HCV infections18. Recent studies revealed that DENV triggered dendritic cell (DC) migration through regulation of the COX-2-dependent signaling cascade, which might facilitate spreading of DENV to different tissues19. The role of COX-2/PGE 2 in DENV replication remains to be investigated.…”