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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. © 2012 Elsevier Ltd.


Documento: Artículo
Título:Underlying mechanisms of cAMP- and glucocorticoid-mediated inhibition of FasL expression in activation-induced cell death
Autor:Liberman, A.C.; Refojo, D.; Antunica-Noguerol, M.; Holsboer, F.; Arzt, E.
Filiación:Laboratorio de Fisiología y Biología Molecular, Departamento de Fisiología y Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires and IBioBA-CONICET, 1428 Buenos Aires, Argentina
Max Planck Institute of Psychiatry, 80804 Munich, Germany
Max Planck Institute of Psychiatry, 80804 Munich, Germany
Palabras clave:Activation-induced cell death; CAMP; Chromatin; FasL; Glucocorticoids; NF-κB; cyclic AMP; cyclic AMP dependent protein kinase; dexamethasone; Fas ligand; genomic DNA; glucocorticoid; immunoglobulin enhancer binding protein; mitogen activated protein kinase; T lymphocyte receptor; animal cell; article; cell death; mouse; nonhuman; priority journal; protein expression; signal transduction; transient transfection; Animals; Apoptosis; Blotting, Western; Cell Death; Cell Separation; Cyclic AMP; Fas Ligand Protein; Flow Cytometry; Glucocorticoids; Humans; Hybridomas; Jurkat Cells; Lymphocyte Activation; Mice; Promoter Regions, Genetic; Receptors, Antigen, T-Cell; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Transfection
Página de inicio:220
Página de fin:235
Título revista:Molecular Immunology
Título revista abreviado:Mol. Immunol.
CAS:cyclic AMP, 60-92-4; dexamethasone, 50-02-2; mitogen activated protein kinase, 142243-02-5; Cyclic AMP, 60-92-4; Fas Ligand Protein; Glucocorticoids; Receptors, Antigen, T-Cell


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---------- APA ----------
Liberman, A.C., Refojo, D., Antunica-Noguerol, M., Holsboer, F. & Arzt, E. (2012) . Underlying mechanisms of cAMP- and glucocorticoid-mediated inhibition of FasL expression in activation-induced cell death. Molecular Immunology, 50(4), 220-235.
---------- CHICAGO ----------
Liberman, A.C., Refojo, D., Antunica-Noguerol, M., Holsboer, F., Arzt, E. "Underlying mechanisms of cAMP- and glucocorticoid-mediated inhibition of FasL expression in activation-induced cell death" . Molecular Immunology 50, no. 4 (2012) : 220-235.
---------- MLA ----------
Liberman, A.C., Refojo, D., Antunica-Noguerol, M., Holsboer, F., Arzt, E. "Underlying mechanisms of cAMP- and glucocorticoid-mediated inhibition of FasL expression in activation-induced cell death" . Molecular Immunology, vol. 50, no. 4, 2012, pp. 220-235.
---------- VANCOUVER ----------
Liberman, A.C., Refojo, D., Antunica-Noguerol, M., Holsboer, F., Arzt, E. Underlying mechanisms of cAMP- and glucocorticoid-mediated inhibition of FasL expression in activation-induced cell death. Mol. Immunol. 2012;50(4):220-235.