Underlying mechanisms of cAMP- and glucocorticoid-mediated inhibition of FasL expression in activation-induced cell death
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...
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2012
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| Acceso en línea: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_01615890_v50_n4_p220_Liberman http://hdl.handle.net/20.500.12110/paper_01615890_v50_n4_p220_Liberman |
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paper:paper_01615890_v50_n4_p220_Liberman2023-06-08T15:13:30Z Underlying mechanisms of cAMP- and glucocorticoid-mediated inhibition of FasL expression in activation-induced cell death Liberman, Ana Refojo, Damián 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 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. Fil:Liberman, A.C. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Refojo, D. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. 2012 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_01615890_v50_n4_p220_Liberman http://hdl.handle.net/20.500.12110/paper_01615890_v50_n4_p220_Liberman |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
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 |
| spellingShingle |
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 Liberman, Ana Refojo, Damián Underlying mechanisms of cAMP- and glucocorticoid-mediated inhibition of FasL expression in activation-induced cell death |
| topic_facet |
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 |
| description |
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. |
| author |
Liberman, Ana Refojo, Damián |
| author_facet |
Liberman, Ana Refojo, Damián |
| author_sort |
Liberman, Ana |
| title |
Underlying mechanisms of cAMP- and glucocorticoid-mediated inhibition of FasL expression in activation-induced cell death |
| title_short |
Underlying mechanisms of cAMP- and glucocorticoid-mediated inhibition of FasL expression in activation-induced cell death |
| title_full |
Underlying mechanisms of cAMP- and glucocorticoid-mediated inhibition of FasL expression in activation-induced cell death |
| title_fullStr |
Underlying mechanisms of cAMP- and glucocorticoid-mediated inhibition of FasL expression in activation-induced cell death |
| title_full_unstemmed |
Underlying mechanisms of cAMP- and glucocorticoid-mediated inhibition of FasL expression in activation-induced cell death |
| title_sort |
underlying mechanisms of camp- and glucocorticoid-mediated inhibition of fasl expression in activation-induced cell death |
| publishDate |
2012 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_01615890_v50_n4_p220_Liberman http://hdl.handle.net/20.500.12110/paper_01615890_v50_n4_p220_Liberman |
| work_keys_str_mv |
AT libermanana underlyingmechanismsofcampandglucocorticoidmediatedinhibitionoffaslexpressioninactivationinducedcelldeath AT refojodamian underlyingmechanismsofcampandglucocorticoidmediatedinhibitionoffaslexpressioninactivationinducedcelldeath |
| _version_ |
1768544681270968320 |