Background Gene association studies examining functional polymorphisms in the immunoregulatory cytokine MIF (macrophage macrophage inhibitory factor, rs5844572) have shown that SLE patients with end-organ sequelae have an increased frequency of high expression MIF genotypes when compared to patients without end-organ involvement. Plasma MIF levels and TLR-stimulated MIF production also reflect underlying MIF genotype. Among activities relevant to autoimmunity, MIF counter-regulates the immunosuppressive action of glucocorticoids, inhibits activation-induced apoptosis, and promotes B cell survival. MIF antagonists show auspicious activity in mouse models of autoimmunity and both anti-MIF (Imalumab) and anti-MIF receptor antibodies (Milatuzamab) have advanced into phase II human clinical testing.
The MIF promoter polymorphism comprises a unique four-nucleotide microsatellite repeat (CATT5–8), with higher repeat number producing increased MIF expression. Because there is no information about the transcriptional regulation of these common alleles, we sought to identify the nuclear protein(s) regulating expression at this functional promoter polymorphism.
Materials and methods We utilised DNA affinity chromatography and liquid chromatography-mass spectrometry analysis to identify unique nuclear proteins that interact with the −794 CATT5–8 MIF promoter polymorphism. Functional knockout, ectopic expression, and −794 CATT-length dependent transcriptional assays and tissue microarray studies confirmed findings.
Results Proteomic analysis identified the transcription factor ICBP90, previously implicated in oncogenesis, as a unique −794 CATT5–8 microsatellite interacting protein. Phosphorylated ICBP90 bound to the MIF promoter in a CATT-length dependent manner and upregulated MIF expression in monocytes, and B and T lymphocytes. Strong correlation was observed between ICBP90 and MIF expression in human inflammatory tissue, with a noteworthy overlap between downstream transcripts regulated by ICBP or MIF.
Conclusions ICBP90 regulates MIF transcription at the −794 MIF CATT5–8 susceptibility locus. Pharmacologic targeting of the ICBP90:CATTx interaction is underway to inhibit MIF promoter overactivity and provide for a structurally-defined, pharmacogenomic approach to treatment.
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