Figure Legends
Figure 1. a. Mechanism of redox regulation by the thioredoxin (Trx) system. The reduced form of Trx catalyses the reduction of disulphide bonds in the target protein. Oxidised thioredoxin is regenerated to the reduced state by the NADPH-dependent flavoenzyme thioredoxin reductase. b. Trx1 inhibition of eosinophil activation and chemotaxis. Trx1 can eliminate reactive oxygen species (ROS) produced by eosinophils and directly inhibit activation of the mitogen-activated protein kinase (MAPK) signal pathway when entering cells. Trx1 regulates the Th2 response by inhibiting IL-13 production, which prevents IL-13 from stimulating epithelial cells or fibroblasts to produce eotaxin. In addition, Trx1 blocks the pro-inflammatory effect of the upstream chemokine macrophage migration inhibitory factor (MIF), which can directly induce the chemotaxis of eosinophils or promote the generation of eotaxin by epithelial cells or fibroblasts to promote eosinophil recruitment.c. Potential mechanism of Trx1 effects on degranulation of mast cells. Crosslinking of the allergen and IgE complex with FcεRI activates the mast cell degranulation pathway, which then activates Lyn, Syk, Btk and phospholipase Cγ (PLCγ). Activation of PLCγ eventually activates Ca2+ and protein kinase c (PKC), which contributes to degranulation. ROS induced in FcεRI-stimulated mast cells activate mast cells by activating PLCγ, Ca2+ influx and PKC. Accordingly, Trx1 prevents mast cell degranulation by scavenging ROS. The effective catalytic function of βII-tryptase secreted by mast cells depends on the existence of normal disulphide bonds in molecules. The Trx1 system selectively reduces the number of disulphide bonds, which reduces the catalytic activity of βII-tryptase.
Figure 2. Thioredoxin-1 (Trx1) regulation of Th1/Th2 balance.Most extracellular cysteine (cys-SH) equivalents exist in the oxidised form of cystine (cys-S-S-cys). T cells cannot ingest cystine and rely on antigen-presenting cells (e.g. dendritic cells) to provide cysteine for them. Dendritic cells convert extracellular cystine into cysteine through Trx secretion, thereby promoting the proliferation of activated T cells. A positive feedback mechanism exists between Trx and IFN-γ, in which Trx1 induces the expression and release of IFN-γ in Th1 cells, and where the increased IFN-γ level in turn increases the Trx1 level. The IFN-γ-activated intracellular Trx1 of macrophages increases the secretion of Th1 cytokine IL-12 by regulating the thiol redox state. Furthermore, Trx1 selectively inactivates the cytokine activity of IL-4 and inhibits the Th2 immune response.
Figure 3. Potential mechanism of thioredoxin-1 (Trx1) inhibition of complement activation. Serum Trx1 inhibits C3 cleavage in alternative pathway alone and enhances FH-induced inhibition of C3 cleavage by combining with FH, which reduces C3a levels and C3b deposition. In contrast, Trx1 on the surface of endothelial cells or serum Trx1 blocks the production and deposition of C5b by inhibiting C5 convertase activity in the three complement terminal pathways; C9 deposition is also inhibited. Simultaneously, Trx1 inhibits the production of anaphylaxis toxin C5a, which reduces the chemotaxis of neutrophils.
Figure 4. a. Thioredoxin-1 (Trx1) improves glucocorticoid (GC) resistance through macrophage migration inhibitory factor (MIF). MIF impairs GC sensitivity via MAP kinase phosphatase-1 (MKP-1) inhibition. MKP-1 is induced by GC to mediate GC inhibition of ERK, JNK and p38MAPK activities as well as cytokine production. MIF inhibits GC-induced leucine zipper (GILZ) expression through a unique set of effects on transcription factor expression and phosphorylation. MKP-1 and MAPK activation are regulated by MIF via GILZ. MIF also affects the NF-κB/IκB signal cascade. Trx1 may directly bind to GC receptor and enhance the response of cells to GCs. Both intracellular and extracellular Trx1 bind to MIF and form a heterodimer to prevent MIF entry into cells and MIF-induced GC resistance. b.Potential clinical applications of Trx1 in allergic diseases.Administration of Trx1 suppresses the excessive allergic inflammatory response. Future clinical applications of Trx1 could include treatment of asthma or allergic rhinitis with a Trx1 inhaler, topical application for patients with contact dermatitis and/or oral delivery for food allergies. It may also be a promising therapeutic strategy to combine Trx1 with corticosteroids. Finally, Trx1 could potentially be administered as an intravenous injection.