Molecular and functional evidence for in vitro cytokine enhancement of human and murine target cell sensitivity to glucocorticoids: TNF-α priming increases glucocorticoid inhibitio...

• Autores: Costas, M.; Trapp, T.; Pereda, M.P.; Sauer, J.; Rupprecht, R.; Nahmod, V.E.; Reul, J.M.H.M.; Holsboer, F.; Arzt, E.
• Año de publicación: 1996
• Idioma: inglés
• Tipo de recurso: artículo
• Fuente: J. CLIN. INVEST. 1996;98(6):1409-1416
• Materia: apoptosis; cytokines; glucocorticoid receptor; glucocorticoid response element; TNF-α; glucocorticoid; tumor necrosis factor alpha; animal cell; apoptosis; article; cytotoxicity; human; human cell; immune response; immunoregulation; mouse; nonhuman; priority journal; target cell; transcription regulation
• Institución: Universidad Nacional de Buenos Aires. Facultad de Ciencias Exactas y Naturales

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-α 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-α also enhanced GR number. The TNF-α effect on transcriptional activity was absent in other cell lines that express TNF-α receptors but not GRs, and became manifest when a GR expression vector was cotransfected, indicating that TNF-α, 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-α 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-α significantly increased the sensitivity to glucocorticoid inhibition of TNF-α-induced cytotoxicity/apoptosis. TNF-α and IL-1β 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.
Fil:Costas, M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.
Fil:Pereda, M.P. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.