title: Molecular and functional evidence for in vitro cytokine enhancement of human and murine target cell sensitivity to glucocorticoids. TNF-alpha priming increases glucocorticoid inhibition of TNF-alpha-induced cytotoxicity/apoptosis.
abstract: Cytokine-induced glucocorticoid secretion and glucocorticoid inhibition of cytokine synthesis and pleiotropic actions act as important safeguards in preventing cytokine overreaction. We found that TNF-alpha increased glucocorticoid-induced transcriptional activity of the glucocorticoid receptor (GR) via the glucocorticoid response elements (GRE) in L-929 mouse fibroblasts transfected with a glucocorticoid-inducible reporter plasmid. In addition, TNF-alpha also enhanced GR number. The TNF-alpha effect on transcriptional activity was absent in other cell lines that express TNF-alpha receptors but not GRs, and became manifest when a GR expression vector was cotransfected, indicating that TNF-alpha, independent of any effect it may have on GR number, has a stimulatory effect on the glucocorticoid-induced transcriptional activity of the GR. Moreover, TNF-alpha increased GR binding to GRE. As a functional biological correlate of this mechanism, priming of L-929 cells with a low (noncytotoxic) dose of TNF-alpha significantly increased the sensitivity to glucocorticoid inhibition of TNF-alpha-induced cytotoxicity/apoptosis. TNF-alpha and IL-1 beta had the same stimulatory action on glucocorticoid-induced transcriptional activity of the GR via the GRE, in different types of cytokine/glucocorticoid target cells (glioma, pituitary, epithelioid). The phenomenon may therefore reflect a general molecular mechanism whereby cytokines modulate the transcriptional activity of the GR, thus potentiating the counterregulation by glucocorticoids at the level of their target cells.
authors.affiliation: Instituto de Investigaciones Médicas, Universidad de Buenos Aires, Argentina.
authors.forename: M
authors.initials: M
authors.lastname: Costas
authors.forename: T
authors.initials: T
authors.lastname: Trapp
authors.forename: M P
authors.initials: MP
authors.lastname: Pereda
authors.forename: J
authors.initials: J
authors.lastname: Sauer
authors.forename: R
authors.initials: R
authors.lastname: Rupprecht
authors.forename: V E
authors.initials: VE
authors.lastname: Nahmod
authors.forename: J M
authors.initials: JM
authors.lastname: Reul
authors.forename: F
authors.initials: F
authors.lastname: Holsboer
authors.forename: E
authors.initials: E
authors.lastname: Arzt
mesh_terms: D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D003907:Dexamethasone / Q000494:pharmacology; D017930:Genes, Reporter; D005938:Glucocorticoids / Q000235:genetics* / Q000276:immunology; D006367:HeLa Cells; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D051379:Mice; D010957:Plasmids; D012333:RNA, Messenger / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000235:genetics* / Q000276:immunology*; D014158:Transcription, Genetic; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D005938:Glucocorticoids; D007375:Interleukin-1; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone