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).