Dual effect of the macrophage migration inhibitory factor gene on the development and severity of human systemic lupus erythematosus

Abstract

Objective To study the effect of the innate cytokine, MIF, on the susceptibility and the severity of SLE in a multinational population of Caucasian and African-American patients. Methods We studied the association between two functional polymorphisms in the MIF gene: a −794 CATT5-8 microsatellite repeat (rs5844572) and a −173 G/C SNP (rs755622), with SLE in 3195 patients and controls. We also measured MIF plasma levels in relation to genotypes, clinical phenotypes, and TLR 7-stimulated MIF production in vitro. Results Both Caucasians and African-Americans with the high expression, −794 CATT7/173*C haplotype had lower SLE incidence (OR 0.63 [0.53, 0.89], p=0.001 in Caucasians, and OR 0.46 [0.23, 0.95], p=0.012 in African-Americans). By contrast, among patients with established SLE, those with nephritis, serositis, and CNS involvement had reduced frequencies of low expression MIF genotypes (−794 CATT5) when compared to patients without end-organ involvement (p=0.005 for serositis, p=0.023 for nephritis, and p=0.04 for CNS involvement). Plasma MIF levels and TLR7 stimulated MIF production in vitro reflected the underlying MIF genotype of the studied groups. Conclusion These data suggest that MIF, which has both pro-inflammatory properties and macrophage and B cell survival functions, exerts a dual influence on the immunopathogenesis of SLE. High expression MIF genotypes are associated with a reduced susceptibility to SLE and may contribute to an enhanced clearance of infectious pathogens. Once SLE develops however, low expression MIF genotypes may protect from ensuing, inflammatory end-organ damage.

Transcription factor ICBP90 regulates the MIF promoter and immune susceptibility locus

“…Both high CATT repeat number and increased MIF expression have been associated with the incidence or clinical severity of different forms of autoimmune arthritis, including rheumatoid arthritis (10)(11)(12). To assess whether ICBP90 is involved in regulating MIF expression in vivo, we examined the expression levels of ICBP90 and MIF mRNA in a registry of synovial tissue samples obtained by synovectomy and subjected previously to whole-tissue microarray analysis.…”

“…Functional studies indicate that CATT repeat number is associated with inducible MIF expression such that the CATT 5 repeat is a low expression allele and the CATT 6 , CATT 7 , and CATT 8 repeats are progressively higher expression alleles (9). These promoter variants occur commonly in the population (minor allele frequency >5%), and higher CATT number is linked to the susceptibility or the clinical severity of autoimmune inflammatory disease (10)(11)(12).…”

“…There is ample evidence that the MIF -794 CATT [5][6][7][8] promoter microsatellite regulates transcription based on gene expression studies and on plasma MIF levels in genotyped individuals with rheumatoid arthritis (10), systemic lupus erythematosus (12), and sepsis (13). To date, however, there is scant information about the molecular regulation of this site under either physiologic or pathologic circumstances.…”

“…Given the low abundance and absence of inflammatory induction of Pit-1 ( Figure 3C), we focused further attention on defining the regulatory role of ICBP90 in -794 CATT 5-8 -dependent MIF expression. MIF production by human monocytes/macrophages or peripheral blood leukocytes is induced by activation of a number of TLRs, including TLR2, TLR4, TLR7, and TLR9 (12,21,30). To assess the functional role of ICBP90 in TLR-activated MIF expression, we measured the transcriptional activity of human THP-1 monocytes transfected with MIF -794 CATT [5][6][7][8] promoter-luciferase fusion plasmids and stimulated them with different TLR ligands in the presence of a control or ICBP90 shRNA.…”

An MIF Promoter Polymorphism Is Associated with Susceptibility to Pulmonary Arterial Hypertension in Diffuse Cutaneous Systemic Sclerosis

“…The promoter region of this gene contains a single nucleotide polymorphism (SNP) at position -173 (rs755622) that has been associated with several immune-mediated diseases, including SSc and systemic lupus erythematosus (SLE) [7][8][9]. This SNP is in high linkage disequilibrium (LD) with a functional polymorphism, a -794 CATT (5-8) microsatellite repeat (rs5844572), also located at the promoter region of the gene [10].…”