4. Trx1 Improves Glucocorticoid Resistance
Glucocorticoids (GCs), which
stabilise mast cells to prevent degranulation and exert broad
anti-inflammatory effects by binding to glucocorticoid receptors (GRs),
are recognised as an effective first-line therapy for allergic diseases.
Notably, however, GCs interfere with the division and proliferation of
systemic lymphoid tissues under the action of antigens, affect the
metabolism of lymphocytes and induce lymphocyte apoptosis. Therefore,
long-term administration of GCs attenuates host immunity to specific
antigens and leads to inhibition of the immune response to pathogenic
microorganisms.
In previous studies, we have shown that the anti-inflammatory and
anti-allergic effects of Trx1 may
inhibit host immunity, in contrast
to the effects of corticosteroids.31,51 Long-term use
of GCs can cause GC resistance or
insensitivity, which is a major barrier to treatment of allergic
diseases. MIF can be induced by GCs and it enhances GC
resistance;99 specifically, it impairs GC sensitivity
via MAP kinase phosphatase-1 (MKP-1) inhibition.100MKP-1 is an important MAPK signal inhibitor that is induced by GCs and
mediates GC inhibition of ERK, JNK and p38 MAPK activities as well as
cytokine production induced by pro-inflammatory stimuli such as LPS or
IL-1.101-103 MIF has been shown to down-regulate
GC-induced leucine zipper (GILZ) expression through a unique set of
effects on transcription factor expression and phosphorylation; notably,
MIF-induced regulation of MKP-1 and MAPK activation is mediated through
GILZ.104 Furthermore, MIF affects the NF-κB/IκB signal
cascade, leading to accentuated inflammation and GC
resistance.105 Trx1 can bind to GR and enhance the
response of cells to glucocorticoids.106 In addition,
it can bind directly to MIF inside and outside the
cell.66 Thus, Trx1 represents a potential intervention
target between GC and MIF balance (Figure 4a).