New insights into the role and mechanism of macrophage migration inhibitory factor in steroid-resistant patients with systemic lupus erythematosus

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.

Association between Macrophage Migration Inhibitory Factor Gene Variation and Response to Glucocorticoid Treatment in Sudden Sensorineural Hearing Loss

“…Therefore, the discovery of glucocorticoid congeners that preserve the immunosuppressive but not the stimulatory activity of MIF will be useful as a novel and more efficient approach for the treatment of inflammatory diseases [Leng et al, 2009]. The correlation between increased MIF level, MIF gene polymorphism and steroid resistance has been reported in several autoimmune diseases and in human CEM (isolated from continuous culture of human lymphoblasts) T-cell lines [Wang et al, 2012].…”

“…In the T-lymphoblast cell line, it has been observed that the presence of the mutant C allele creates an AP-4 transcription factor binding site, resulting in a significantly increased MIF expression. It has also been reported that increased MIF concentration was associated with more severe clinical presentations and subsequently a poor outcome of the disease [Renner et al, 2005;Arikan et al, 2006;Wang et al, 2012;Bucala, 2013;Yazdani et al, 2013]. In contrast to other proinflammatory cytokines that are generally suppressed by glucocorticoids, MIF has a very specific counterregulatory effect on glucocorticoids.…”

“…The mechanism of the MIF counterregulatory effect on the anti-inflammatory actions of glucocorticoid is not yet fully understood. However, MIF and glucocorticoids may interact with each other through several different pathways [Vivarelli et al, 2008;Wang et al, 2012].…”

“…Although T cells are known as the main source of MIF production, other cell types including macrophages are also involved in MIF production and secretion. MIF is also considered as a proinflammatory cytokine with a range of targets which modulate the expression of a number of inflammatory molecules, including TNF-α, IL-6, IL-1b, IL-2, IL-8, and IFN-γ [Wang et al, 2012;Zhang et al, 2013] and playing an important immune regulatory role in several inflammatory diseases such as rheumatoid arthritis and atherosclerosis [Xiao et al, 2011;Saeedi et al, 2013].…”

A Role for Receptor-Interacting Protein Kinase-1 in Neutrophil Extracellular Trap Formation in Patients with Systemic Lupus Erythematosus: a Preliminary Study

“…However, accumulating data support that although RIPK1 and RIPK3 kinases first emerged as mediators of necroptosis, they also promote caspase-8-dependent apoptosis and proinflammatory gene expression [12-14]. RIPK1 and RIPK3 promote at least three distinct responses: necroptosis, apoptosis, and cell death-independent inflammation, and the loss of homeostasis of any of these pathways may contribute to the development of pathology [12, 15, 16]. Therefore, the aim of this study is to determine RIPK1 expression and investigate whether RIPK1 contributes to NETs formation in SLE patients.…”