Table 1: Summary of the main cytokines associated with development of DHF/DSS and their biological function in relation to pathogenesis.

CytokinesBiological functionRefs.

MCP-1Monocyte chemoattractant protein-1 is critical to drive the extravasation of mononuclear cells into the inflamed, infected, and traumatized sites of infection. In addition, it promotes endothelial permeability increasing the vascular leakage as a result of dengue virus infection.[47, 48]

IL-1It induces tissue factor (TF) expression of endothelial cells (EC) and suppresses their cell surface anticoagulant activity. It may upregulate TNF-α production and activity. IL-1β mediates platelet-induced activation of ECs, which increases chemokine release and upregulates VCAM-1 enhancing adhesion of monocytes to the endothelium. [43, 49]

IL-6It has been described as a strong inducer of endothelial permeability resulting in vascular leakage. IL-6 potentiates the coagulation cascade and can downregulate production of TNF-α and its receptors. IL-6 may perform a synergistic role with some pyrogens such as IL-1 to induce fever.[50, 51]

IL-8Its systemic concentrations are increased by EC damage, which in turn induces endothelial permeability. Activation of the coagulation system results in increased expression of IL-6 and IL-8 by monocytes, while the APC anticoagulation pathway downregulates the production of IL-8 by ECs.[49, 50, 52]

IL-10It plays an immunosuppressive role that causes IFN resistance, followed by impaired immune clearance and a persistent infectious effect for acute viral infection. IL-10 also inhibits the expression of TF and inhibits fibrinolysis. IL-10 plasma levels have been associated with disease severity; however, its role in dengue pathogenesis has not been fully elucidated.[53]

TNF-αIt is a potent activator of ECs; it enhances capillary permeability. TNF-α upregulates expression of TF in monocytes and ECs and downregulates expression of thrombomodulin on ECs. It also activates the fibrinolytic system and enhances expression of NO mediating activation-induced death of T cells, and it has therefore been implicated in peripheral T-cell deletion.[49, 51, 54]

TGF-βEarly in infection, low levels of TGF-β may trigger secretion of IL-1 and TNF-β. However, later in infection, the cytokine inhibits the Th1 response and enhances production of Th2 cytokines such as IL-10. TGF-β increases expression of TF on ECs and upregulates expression and release of PAI-1 (plasminogen activator inhibitor-1).[3]

VEGFVEGF is a key driver of vascular permeability. It reduces EC occludins, claudins, and the VE-cadherin content, all of which are components of ECs junctions. Upon activation, VEGF stimulates expression of ICAM-1, VCAM-1, and E-selectin in ECs.[3, 36]