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

Background Macrophage migration inhibitory factor (MIF) is an inflammatory and neurorendocrine mediator that counter-regulates 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 upregulated by glucocorticoids, which serves as a physiologic regulator of the inflammatory responses. This study defined interactions between the MIF promoter, the glucocorticoid receptor (GR), and the transcription factor ICBP90, which binds to the promoter in a -794 CATT5-8 -length dependent manner, to regulate MIF transcription. Methods Interactions between ICBP90, GR, and AP-1 with MIF -794 CATT5-8 promoter constructs were assessed by co-immunoprecipitation, Western blotting, and genetic knockdown. Nuclear co-localization was 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 upregulated MIF transcription in a -794 CATT5-8 length-dependent manner. Experimental reduction in 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 support a mechanism for genetic variation of glucocorticoid-regulated MIF transcription with implications for autoimmune disease severity and glucocorticoid responsiveness.