Non-canonical Glucocorticoid Receptor Transactivation of gilz by Alcohol Suppresses Cell Inflammatory Response
Acute alcohol exposure suppresses cell inflammatory response. The underlying mechanism has not been fully defined. Here we report that alcohol was able to activate glucocorticoid receptor (GR) signaling in the absence of glucocorticoids (GCs) and upregulated glucocorticoid-induced leucine zipper (gi...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2017-06-01
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| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | http://journal.frontiersin.org/article/10.3389/fimmu.2017.00661/full |
| _version_ | 1818693548499795968 |
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| author | Hang Pong Ng Scott Jennings Jack Wang Patricia E. Molina Steve Nelson Guoshun Wang |
| author_facet | Hang Pong Ng Scott Jennings Jack Wang Patricia E. Molina Steve Nelson Guoshun Wang |
| author_sort | Hang Pong Ng |
| collection | DOAJ |
| description | Acute alcohol exposure suppresses cell inflammatory response. The underlying mechanism has not been fully defined. Here we report that alcohol was able to activate glucocorticoid receptor (GR) signaling in the absence of glucocorticoids (GCs) and upregulated glucocorticoid-induced leucine zipper (gilz), a prominent GC-responsive gene. Such a non-canonical activation of GR was not blocked by mifepristone, a potent GC competitor. The proximal promoter of gilz, encompassing five GC-responsive elements (GREs), was incorporated and tested in a luciferase reporter system. Deletion and/or mutation of the GREs abrogated the promoter responsiveness to alcohol. Thus, the GR–GRE interaction transduced the alcohol action on gilz. Alcohol induced GR nuclear translocation, which was enhanced by the alcohol dehydrogenase inhibitor fomepizole, suggesting that it was alcohol, not its metabolites, that engendered the effect. Gel mobility shift assay showed that unliganded GR was able to bind GREs and such interaction withstood clinically relevant levels of alcohol. GR knockout via CRISPR/Cas9 gene targeting or GILZ depletion via small RNA interference diminished alcohol suppression of cell inflammatory response to LPS. Thus, a previously unrecognized, non-canonical GR activation of gilz is involved in alcohol modulation of cell immune response. |
| first_indexed | 2024-12-17T13:15:26Z |
| format | Article |
| id | doaj.art-2d48df9171b54407b852b0e66bcb0acc |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-17T13:15:26Z |
| publishDate | 2017-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-2d48df9171b54407b852b0e66bcb0acc2022-12-21T21:47:01ZengFrontiers Media S.A.Frontiers in Immunology1664-32242017-06-01810.3389/fimmu.2017.00661272789Non-canonical Glucocorticoid Receptor Transactivation of gilz by Alcohol Suppresses Cell Inflammatory ResponseHang Pong Ng0Scott Jennings1Jack Wang2Patricia E. Molina3Steve Nelson4Guoshun Wang5Alcohol and Drug Abuse Center, Department of Microbiology, Immunology and Parasitology, Louisiana State University Health Sciences Center, New Orleans, LA, United StatesAlcohol and Drug Abuse Center, Department of Microbiology, Immunology and Parasitology, Louisiana State University Health Sciences Center, New Orleans, LA, United StatesAlcohol and Drug Abuse Center, Department of Microbiology, Immunology and Parasitology, Louisiana State University Health Sciences Center, New Orleans, LA, United StatesDepartment of Physiology, Louisiana State University Health Sciences Center, New Orleans, LA, United StatesDepartment of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, United StatesAlcohol and Drug Abuse Center, Department of Microbiology, Immunology and Parasitology, Louisiana State University Health Sciences Center, New Orleans, LA, United StatesAcute alcohol exposure suppresses cell inflammatory response. The underlying mechanism has not been fully defined. Here we report that alcohol was able to activate glucocorticoid receptor (GR) signaling in the absence of glucocorticoids (GCs) and upregulated glucocorticoid-induced leucine zipper (gilz), a prominent GC-responsive gene. Such a non-canonical activation of GR was not blocked by mifepristone, a potent GC competitor. The proximal promoter of gilz, encompassing five GC-responsive elements (GREs), was incorporated and tested in a luciferase reporter system. Deletion and/or mutation of the GREs abrogated the promoter responsiveness to alcohol. Thus, the GR–GRE interaction transduced the alcohol action on gilz. Alcohol induced GR nuclear translocation, which was enhanced by the alcohol dehydrogenase inhibitor fomepizole, suggesting that it was alcohol, not its metabolites, that engendered the effect. Gel mobility shift assay showed that unliganded GR was able to bind GREs and such interaction withstood clinically relevant levels of alcohol. GR knockout via CRISPR/Cas9 gene targeting or GILZ depletion via small RNA interference diminished alcohol suppression of cell inflammatory response to LPS. Thus, a previously unrecognized, non-canonical GR activation of gilz is involved in alcohol modulation of cell immune response.http://journal.frontiersin.org/article/10.3389/fimmu.2017.00661/fullglucocorticoid receptorglucocorticoid-induced leucine zipperglucocorticoidalcoholLPSinflammatory response |
| spellingShingle | Hang Pong Ng Scott Jennings Jack Wang Patricia E. Molina Steve Nelson Guoshun Wang Non-canonical Glucocorticoid Receptor Transactivation of gilz by Alcohol Suppresses Cell Inflammatory Response Frontiers in Immunology glucocorticoid receptor glucocorticoid-induced leucine zipper glucocorticoid alcohol LPS inflammatory response |
| title | Non-canonical Glucocorticoid Receptor Transactivation of gilz by Alcohol Suppresses Cell Inflammatory Response |
| title_full | Non-canonical Glucocorticoid Receptor Transactivation of gilz by Alcohol Suppresses Cell Inflammatory Response |
| title_fullStr | Non-canonical Glucocorticoid Receptor Transactivation of gilz by Alcohol Suppresses Cell Inflammatory Response |
| title_full_unstemmed | Non-canonical Glucocorticoid Receptor Transactivation of gilz by Alcohol Suppresses Cell Inflammatory Response |
| title_short | Non-canonical Glucocorticoid Receptor Transactivation of gilz by Alcohol Suppresses Cell Inflammatory Response |
| title_sort | non canonical glucocorticoid receptor transactivation of gilz by alcohol suppresses cell inflammatory response |
| topic | glucocorticoid receptor glucocorticoid-induced leucine zipper glucocorticoid alcohol LPS inflammatory response |
| url | http://journal.frontiersin.org/article/10.3389/fimmu.2017.00661/full |
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