ICBP90 Regulates MIF Expression, Glucocorticoid Sensitivity, and Apoptosis at the MIF Immune Susceptibility Locus

Abstract

Objective Macrophage migration inhibitory factor (MIF) is an inflammatory and neurorendocrine mediator that counterregulates glucocorticoid immunosuppression. MIF polymorphisms, which comprise a variant promoter microsatellite (−794 CATT5–8), are linked genetically to autoimmune disease severity and to glucocorticoid resistance. While invasive stimuli increase MIF expression, MIF also is up‐regulated by glucocorticoids, which serve as a physiologic regulator of inflammatory responses. This study was undertaken to define interactions between the MIF promoter, the glucocorticoid receptor (GR), and the transcription factor inverted CCAAT box binding protein 90 kd (ICBP90) (also referred to as UHRF1), which binds to the promoter in a −794 CATT5–8 length–dependent manner, to regulate MIF transcription. Methods Interactions of ICBP90, GR, and activator protein 1 (AP‐1) with MIF −794 CATT5–8 promoter constructs were assessed by coimmunoprecipitation, Western blotting, and genetic knockdown. Nuclear colocalization studies were performed using anti–transcription factor antibodies and confocal microscopy of glucocorticoid‐treated cells. MIF transcription was studied in CEM‐C7 T cells, and the impact of the MIF −794 CATT5–8 microsatellite variation confirmed in peripheral blood T cells and in rheumatoid synovial fibroblasts of defined MIF genotype. Functional interactions were quantified by apoptosis and apoptotic signaling in high‐ and low‐genotypic MIF–expressing human cells. Results We defined functional interactions between the transcription factors ICBP90, the GR, and AP‐1 that up‐regulated MIF transcription in a −794 CATT5–8 length–dependent manner. Experimental reduction of ICBP90, GR, or AP‐1 decreased MIF expression and increased glucocorticoid sensitivity, leading to enhanced apoptosis in T lymphocytes and in rheumatoid synovial fibroblasts. Conclusion These findings suggest a mechanism for genetic variation of glucocorticoid‐regulated MIF transcription, with implications for autoimmune disease severity and glucocorticoid responsiveness.

D‐dopachrome tautomerase in cardiovascular and inflammatory diseases—A new kid on the block or just another MIF?

“…Moreover, glucocorticoids (involving the GRE and ATF/CRE transcription factor binding sites), peptide hormones, cancerogenic stress, and glucose have also been implicated in controlling MIF gene expression 75,76 . Importantly, analysis of upstream regulatory regions has revealed a key role for the ‐794 CATT 5‐8 microsatellite and the transcription factor ICBP90 as well as the ‐173‐G/C SNP in controlling MIF gene expression 29,77–79 . In comparison, little is known about the regulation of MIF‐2 gene expression and the regulated secretion of this MIF homolog.…”

“…75,76 Importantly, analysis of upstream regulatory regions has revealed a key role for the -794 CATT 5-8 microsatellite and the transcription factor ICBP90 as well as the -173-G/C SNP in controlling MIF gene expression. 29,[77][78][79] In comparison, little is known about the regulation of MIF-2 gene expression and the regulated secretion of this MIF homolog. For example, upstream regulatory elements or microsatellites such as -794 CATT 5-8 have not been identified for the MIF-2 gene.…”

Macrophage migration inhibitory factor in acute kidneyinjury

“…Basal MIF expression is regulated by the transcription factorspecific protein1 (SP1) (Roger et al, 2007), cAMP response element binding protein (CREB) (Weiser et al, 1989)and NF-κB regulation (Chen et al, 2009). What's more, ICBP90 (Yao et al, 2021)and HIF1-α can up-regulate the transcription level of MIF (Welford et al, 2006;Zis et al, 2015;Safi et al, 2020). Expressed in different tissues and cells, MIF acts different roles in many diseases, such as tumors (Du et al, 2013;Fukaya et al, 2016), autoimmune diseases (Hernandez-Palma et al, 2019) and acute organ injury (Djudjaj et al, 2017;Ochi et al, 2017) (Liu et al, 2021).…”

MIF contribution to progressive brain diseases

“…MIF, a multifaceted cytokine is involved in immune response and numerous biological processes like proliferation, angiogenesis, anti-oxidant signaling and tissue repair [ 11 , 12 ]. MIF has been identified as a critical controller of inflammation and immune responses by counter-regulating immunosuppressive effect of glucocorticoids [ 8 , 13 – 15 ]. Production during systemic inflammation and glucocorticoid regulatory abilities of MIF are in tight conjunction with the hypothalamic–pituitary–adrenal axis.…”