An emerging role for the anti-inflammatory cytokine interleukin-10 in dengue virus infection

Abstract

Infection with dengue virus (DENV) causes both mild dengue fever and severe dengue diseases, such as dengue hemorrhagic fever and dengue shock syndrome. The pathogenic mechanisms for DENV are complicated, involving viral cytotoxicity, immunopathogenesis, autoimmunity, and underlying host diseases. Viral load correlates with disease severity, while the antibody-dependent enhancement of infection largely determines the secondary effects of DENV infection. Epidemiological and experimental studies have revealed an association between the plasma levels of interleukin (IL)-10, which is the master anti-inflammatory cytokine, and disease severity in patients with DENV infection. Based on current knowledge of IL-10-mediated immune regulation during infection, researchers speculate an emerging role for IL-10 in clinical disease prognosis and dengue pathogenesis. However, the regulation of dengue pathogenesis has not been fully elucidated. This review article discusses the regulation and implications of IL-10 in DENV infection. For future strategies against DENV infection, manipulating IL-10 may be an effective antiviral treatment in addition to the development of a safe dengue vaccine.

Figure 1

Theoretical model for IL-10 production and its pathogenic role during DENV infection. IL-10 is produced in T cells (T_H2 and Treg) through an unknown mechanism and in Fcγ receptor-bearing cells directly through viral receptors and indirectly through an ADE-facilitated manner. The extrinsic ADE pathway occurs through Fcγ receptor-facilitated virus contact and entry following viral receptor-mediated endocytosis. An alternative intrinsic ADE pathway may trigger Fcγ receptor-mediated signaling to activate Syk/PKC/ERK-regulated IL-10 expression. However, the molecular mechanisms for IL-10 production remain unclear. Crosstalk between PKC/PKA/PKB-regulated GSK-3 for the transcriptional regulation of IL-10 and the involvement of genetic factors are also summarized. IL-10-regulated SOCS3 expression may benefit DENV replication by facilitating IFN resistance.