Proinflammatory cytokines regulate human glucocorticoid receptor gene expression and lead to the accumulation of the dominant negative beta isoform: A mechanism for the generation of glucocorticoid resistance

Inflammatory responses in many cell types are coordinately regulated by the opposing actions of NF-kappaB and the glucocorticoid receptor (GR), The hu man glucocorticoid receptor (hGR) gene encodes two protein isoforms: a cyto plasmic alpha form (GR alpha), which binds hormone, translocates to the nuc leus, and regulates gene transcription, and a nuclear localized beta isofor m (GRP), which does not bind known ligands and attenuates GR alpha action. We report here the identification of a tumor necrosis factor (TNF)responsiv e NF-kappaB DNA binding site 5' to the hCR promoter that leads to a 1.5-fol d increase in GR alpha mRNA and a 2.0-fold increase in GRP mRNA in HeLa53 c ells, which endogenously express both GR isoforms, However, TNF-alpha treat ment disproportionately increased the steady-state levels of the GR beta pr otein isoform over GR alpha, making GR beta the predominant endogenous rece ptor isoform, Similar results were observed following treatment of human CE MC7 lymphoid cells with TNF-alpha or IL-1, The increase in GRP protein expr ession correlated with the development of glucocorticoid resistance.