Summary of soluble factors that are or are likely to be associated with development of DHF/DSS

Soluble factorBiological function in relation to pathogenesis
ThrombinThrombin is thought to act near the site at which it is produced. Thrombin converts circulating fibrinogen to fibrin and triggers platelet activation, which results in platelet aggregation. Thrombin activates EC and increases EC permeability, leading to plasma leakage and edema formation. Thrombin is chemotactic for monocytes and is mitogenic for lymphocytes and mesenchymal cells. Activated platelets release several soluble factors with inflammatory, antimicrobial, and immune modulating activity, such as MMP-9, which enhances EC permeability. Activated platelets also secrete soluble CD40 ligand, which can induce EC to produce reactive oxygen species, adhesion molecules, chemokines, and TF. Thrombin also inhibits IL-12 production by mononuclear cells.
C3a and C5aC3a activates platelets and enhances their activation and adhesion properties. C5a enhances blood thrombogenicity by upregulating TF and PAI-1 expression on various cell types. C5a stimulates monocytes to produce IL-1, IL-6, IL-8, and TNF-α. Activation of these complement factors is enhanced by thrombin, which cleaves C3 and C5 to C3a/b and C5a/b, respectively. Activated platelets are also involved in C3 cleavage, which induces activation of the classical complement pathway.
C4bC4b binds to protein S and thereby inhibit the anticoagulant properties of activated protein C-protein S complexes.
IL-1IL-1β is major mediator of platelet-induced activation of EC, causing enhanced chemokine release and upregulation of VCAM-1. VCAM-1 promotes adhesion of monocytes to the endothelium. IL-1 increases the expression of TF on EC and suppresses the cell surface anticoagulant activity of EC. Depending on its concentration, it may upregulate TNF-α production or downregulate TNF-receptors. IL-1 stimulates the hypothalamus and, as a consequence, the pituitary gland to produce anti-inflammatory mediators such as endorphins, melanocyte-stimulating hormone, and adrenocorticotropic hormone.
IL-6Together with other proinflammatory cytokines, IL-6 potentiates the coagulation cascade. It can downregulate production of TNF-α and TNF receptors. IL-6, together with IL-1, is a potent inducer of fever.
IL-8IL-8 is a chemokine that is abundantly produced by monocytes, EC, and hepatocytes. EC damage in the liver may elevate systemic concentrations. Activation of the coagulation system results in increased expression of IL-6 and IL-8 by monocytes, while the APC-PS anticoagulation pathway downregulates production of IL-8 by EC.
IL-10IL-10 is produced by monocytes and regulatory T helper cells and may cause platelet decay. Thrombin can stimulate IL-10 production by monocytes. The cytokine downregulates the inflammatory response and creates a proviral survival milieu. IL-10 promotes OAS by inhibiting development of effector T cells to new epitopes. IL-10 also inhibits the expression of TF and inhibits fibrinolysis.
TNF-αTNF-α in a potent activator of EC and enhances capillary permeability. TNF-α upregulates expression of TF on monocytes and EC and downregulates expression of thrombomodulin on EC. It also activates the fibrinolysis system. TNF-α enhances expression of NO and mediates activation-induced death of T cells, and it has therefore been implicated in peripheral T-cell deletion.
TGF-βTGF-β may act as a proinflammatory or anti-inflammatory cytokine, depending on its concentration. Early in infection, low levels of TGF-β may trigger secretion of IL-1 and TNF-α. 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 EC and upregulates expression and release of PAI-1.
NONO has a multifaceted role in inflammatory reactions. It enhances vasodilatation and formation of edema. It upregulates TNF-α production in monocytes. At low concentrations it protects cells from apoptosis, while at high concentrations it induces apoptosis. NO downregulates expression of MHC class II and suppresses expansion of Th1 cells. Maintenance of the EC barrier requires a basal level of NO. Both a lack of NO and high NO levels destabilize EC junctions.
VEGFVEGF is a key driver of vascular permeability. It reduces EC occludins, claudins, and VE-cadherin content, all of which are components of EC junctions. Upon activation, VEGF stimulates expression of ICAM-1, VCAM-1, and E-selectin in EC.