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.