Negative regulation of interleukin 2 transcription by the glucocorticoid receptor.
Glucocorticoid-dependent transcriptional enhancement is known to occur through the interaction of the glucocorticoid receptor (GR) with specific DNA response elements. In contrast, negative regulation of gene expression by this class of hormone is less well understood. Glucocorticoids are potent immunosuppressive agents acting primarily by inhibiting T lymphocyte activation and lymphokine production. Interleukin 2 (IL-2) gene expression, a critical early event during T lymphocyte activation, is inhibited in glucocorticoid-sensitive cells by hormone treatment. We have studied the mechanism of this inhibition. In transgenic mice carrying c-myc linked to the IL-2 enhancer, mitogen-induced expression of the transgene is inhibited by concurrent glucocorticoid treatment, while a similar transgene construct driven by three copies of the binding site for nuclear factor of activated T cells is not inhibited. Cotransfection experiments into glucocorticoid-insensitive jurkat cells show that the NH2 terminus of the glucocorticoid receptor is dispensable for inhibition of the IL-2 enhancer but that an intact DNA binding domain, although not necessarily binding to DNA, is required. Hybrid GRs containing the DNA binding domains of either the estrogen receptor (ER) or thyroid receptor, as well as the entire wild-type ER, all function as repressors of the IL-2 enhancer. We have localized the site of inhibition to two sequences located in the proximal half of the enhancer. These sequences bind a similar, if not identical, inducible nuclear factor that has biologic characteristics that distinguish it from AP-1. The mechanism of IL-2 inhibition likely involves direct interactions between the GR and this factor.
Northrop
J P
JP
Department of Pathology, Stanford University School of Medicine, California 94305.
Crabtree
G R
GR
Mattila
P S
PS
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D010957:Plasmids; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D007376:Interleukin-2; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone