title: Underlying mechanisms of cAMP- and glucocorticoid-mediated inhibition of FasL expression in activation-induced cell death.
abstract: Glucocorticoids (GCs) and cAMP-dependent signaling pathways exert diverse and relevant immune regulatory functions, including a tight control of T cell death and homeostasis. Both of these signaling molecules inhibit TCR-induced cell death and FasL expression, but the underlying mechanisms are still poorly understood. Therefore, to address this question, we performed a comprehensive screening of signaling pathways downstream of the TCR, in order to define which of them are targets of cAMP- and GC-mediated inhibition. We found that cAMP inhibited NF-κB and ERK pathways through a PKA-dependent mechanism, while Dexamethasone blocked TCR-induced NF-κB signaling. Although GCs and cAMP inhibited the induction of endogenous FasL mRNA expression triggered by TCR activation, they potentiated TCR-mediated induction of FasL promoter activity in transient transfection assays. However, when the same FasL promoter was stably transfected, the facilitatory effect of GCs and cAMP became inhibitory, thus resembling the effects on endogenous FasL mRNA expression. Hence, the endogenous chromatinization status known to occur in integrated or genomic vs. episomic DNA might be critical for proper regulation of FasL expression by cAMP and GCs. Our results suggest that the chromatinization status of the FasL promoter may function as a molecular switch, controlling cAMP and GC responsiveness and explaining why these agents inhibit FasL expression in T cells but induce FasL in other cell types.
authors.affiliation: Laboratorio de Fisiología y Biología Molecular, Departamento de Fisiología y Biología Molecular y Celular, Universidad de Buenos Aires and IBioBA-CONICET, 1428 Buenos Aires, Argentina.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Liberman
authors.forename: Damian
authors.initials: D
authors.lastname: Refojo
authors.forename: Maria
authors.initials: M
authors.lastname: Antunica-Noguerol
authors.forename: Florian
authors.initials: F
authors.lastname: Holsboer
authors.forename: Eduardo
authors.initials: E
authors.lastname: Arzt
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D015153:Blotting, Western; D016923:Cell Death; D002469:Cell Separation; D000242:Cyclic AMP / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D053222:Fas Ligand Protein / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D005434:Flow Cytometry; D005938:Glucocorticoids / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D006825:Hybridomas; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D051379:Mice; D011401:Promoter Regions, Genetic / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000187:drug effects / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D014162:Transfection
chemical_list: D053222:Fas Ligand Protein; D005938:Glucocorticoids; D011948:Receptors, Antigen, T-Cell; D000242:Cyclic AMP