Abstract
IntroductionGlucocorticoid (GC) therapy remains important in improving the prognosis of patients with systemic lupus erythematosus (SLE). However, some patients do not achieve an effective response with GC treatment, creating an obstacle to the remission of SLE. Identification of the underlying mechanisms responsible for steroid resistance can be significant. Macrophage migration inhibitory factor (MIF) arouses our interest because of its reciprocal relationship with GCs. In the present study, we investigated for the first time whether MIF correlated with steroid resistance in SLE and explored potential mechanisms of action.MethodsSixty-two patients with SLE (40 steroid sensitive and 22 steroid resistant) and 21 normal controls were recruited. Serum levels of MIF were measured by ELISA. Cytosolic MIF and IκB expression in peripheral blood mononuclear cells (PBMCs) were determined by western blotting. The electrophoretic mobility shift assay was assessed by NF-κB in nuclear aliquots. Gene silencing was applied to reduce expression of MIF in PBMCs in steroid-resistant patients. PBMCs obtained from steroid-sensitive patients were treated with recombinant human MIF of different concentrations.ResultsMIF levels in serum and PBMCs were higher in steroid-resistant patients compared with steroid-sensitive patients and controls. In contrast to the steroid-sensitive group, NF-κB levels were significantly higher and IκB levels lower in steroid-resistant patients. After MIF gene silencing, IκB levels in cells from steroid-resistant patients were increased. In steroid-sensitive patients, a decrease in IκB levels and an increase in NF-κB expression from baseline were detected in PBMCs treated with a higher concentration of recombinant human MIF. Treatment with recombinant human MIF did not regulate expression of IκB and NF-κB in PBMCs from patients treated with an anti-MIF monoclonal antibody.ConclusionsOur results indicated that MIF may play a role in the formation of steroid resistance in SLE by affecting the NF-κB/IκB signaling cascade. As a regulator of glucocorticoid sensitivity, MIF may be a potential target for steroid sparing.
Highlights
Glucocorticoid (GC) therapy remains important in improving the prognosis of patients with systemic lupus erythematosus (SLE)
In steroid-sensitive patients, a decrease in IB levels and an increase in nuclear factor (NF)-B expression from baseline were detected in peripheral blood mononuclear cell (PBMC) treated with a higher concentration of recombinant human migration inhibitory factor (MIF)
Treatment with recombinant human MIF did not regulate expression of IB and NF-B in PBMCs from patients treated with an anti-MIF monoclonal antibody
Summary
Glucocorticoid (GC) therapy remains important in improving the prognosis of patients with systemic lupus erythematosus (SLE). Macrophage migration inhibitory factor (MIF) arouses our interest because of its reciprocal relationship with GCs. In the present study, we investigated for the first time whether MIF correlated with steroid resistance in SLE and explored potential mechanisms of action. In murine antigen-induced arthritis, GC inhibition of histological severity of disease is reversed by exogenous MIF [8]. Consistent with this finding, Leech and colleagues reported that increased joint inflammation and lethality can be overridden by the neutralization of MIF in the absence of GC in rat adjuvant-induced arthritis [9]. Several studies to date have revealed that deficiency of MIF, either through genetic deletion or by the anti-sense oligonucleotide, leads to a left-shift in the dose response to GC of macrophage TNF production, which represents the fact that MIF does directly regulate GC sensitivity [6,12]
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