3.1 Eliminating Reactive Oxygen Species and Maintaining Redox
Balance
Trx1 can directly remove ROS produced in inflamed tissues and help
maintain redox balance.30 Mitsui et al. showed
that Trx1 transgenic mice had strong resistance to oxidative stress and
a longer life span compared with wild-type (WT)
animals.54 Compared with the Trx1 system, the
intracellular redox system has similar anti-oxidant mechanisms, such as
the glutathione and peroxidase systems, which defend against oxidative
stress. The Trx1 and glutathione systems act as backup systems to
provide electrons for each other, i.e. the two systems protect cells
from oxidative damage synergistically.55,56 In
addition, Trx1 is required to provide electrons when peroxidase is used
to reduce ROS in organisms.57 Thus, Trx1 plays a key
role in the balance of multiple redox systems in the body, and it
coordinates the normal operation and function of these systems.
In the allergic state, expression of Trx1 can be induced to reduce the
damage caused by excessive ROS. Simultaneously, the Trx1 system restores
and refolds oxidised and damaged proteins. Consequently, Trx1 likely
plays an important protective role against allergic inflammation.
3.2 Inhibition of
MIF
Human MIF, a member of the Trx1 family of proteins that displays thiol
reductase activity, was first cloned from T cells in
1989.58 It has inhibitory properties on the migration
of macrophages and plays an essential role in cellular immunity,
especially in delayed-type hypersensitivity.59 MIF is
largely regarded as a pleiotropic inflammatory medium with a wide range
of immunoregulatory and pro-inflammatory activities, including the
induction of inflammatory cytokines, regulation of macrophage and
lymphocyte proliferation and functions similar to those of
chemokines.59,60 Furthermore, MIF is directly involved
in eosinophil differentiation, survival, activation and
migration.18
MIF shares the redox-active motif -Cys-Xxx-Xxx-Cys- with
Trx1.61 It has sulfhydryl reductase activity and
direct redox reactions with Trx1.62 Several
preclinical studies using animal models have found that Trx has
beneficial protective functions against various inflammatory diseases.
For example, the serum MIF level of Trx1 transgenic mice was
significantly lower than that of WT mice in a dextran sodium
sulphate-induced colitis mouse model.63 In mice with
systemic inflammatory reactions caused by smoking, MIF gene expression
in the spleens of Trx1 transgenic mice was inhibited compared with the
expression levels in control mice.64 Using a mouse
model of asthma, Torii et al. found that MIF production in the
lungs of Trx1 transgenic mice was significantly reduced despite similar
systemic Th2 responses and IgE concentrations, indicating that Trx1 can
suppress airway inflammation by directly inhibiting MIF independent of
systemic Th1/Th2 immune modulation.24
In vitro studies have provided direct evidence for the strong
anti-MIF effect of Trx1. For instance, the production of MIF in
macrophages cultured with LPS and IFN-γ was significantly inhibited by
Trx1.63 MIF expression is also suppressed in
Trx1-transfected cells,65 and topically applied
exogenous Trx1 suppresses the expression of MIF in ICD skin
tissues.33 Additionally, MIF can enter cells to induce
a series of inflammatory reactions, and cell surface Trx1 is one of the
target proteins for MIF internalisation. Specifically, membrane-located
Trx1, on the cell surface, binds extracellular MIF with high affinity
and blocks MIF internalisation. Exogenous and intracellular Trx1 can
also directly bind to MIF, thereby forming a complex that blocks the
MIF-induced inflammatory response.66