Cargando…

TNFα-mediated Hsd11b1 binding of NF-κB p65 is associated with suppression of 11β-HSD1 in muscle

The activity of the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which converts inactive cortisone (11-dehydrocorticosterone (11-DHC)) (in mice) into the active glucocorticoid (GC) cortisol (corticosterone in mice), can amplify tissue GC exposure. Elevated TNFα is a common feature in a...

Descripción completa

Detalles Bibliográficos
Autores principales: Doig, Craig L, Bashir, Jamila, Zielinska, Agnieszka E, Cooper, Mark S, Stewart, Paul M, Lavery, Gareth G
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioScientifica 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4027025/
https://www.ncbi.nlm.nih.gov/pubmed/24413279
http://dx.doi.org/10.1530/JOE-13-0494
_version_ 1782316939103698944
author Doig, Craig L
Bashir, Jamila
Zielinska, Agnieszka E
Cooper, Mark S
Stewart, Paul M
Lavery, Gareth G
author_facet Doig, Craig L
Bashir, Jamila
Zielinska, Agnieszka E
Cooper, Mark S
Stewart, Paul M
Lavery, Gareth G
author_sort Doig, Craig L
collection PubMed
description The activity of the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which converts inactive cortisone (11-dehydrocorticosterone (11-DHC)) (in mice) into the active glucocorticoid (GC) cortisol (corticosterone in mice), can amplify tissue GC exposure. Elevated TNFα is a common feature in a range of inflammatory disorders and is detrimental to muscle function in diseases such as rheumatoid arthritis and chronic obstructive pulmonary disease. We have previously demonstrated that 11β-HSD1 activity is increased in the mesenchymal stromal cells (MSCs) by TNFα treatment and suggested that this is an autoregulatory anti-inflammatory mechanism. This upregulation was mediated by the P2 promoter of the Hsd11b1 gene and was dependent on the NF-κB signalling pathway. In this study, we show that in contrast to MSCs, in differentiated C2C12 and primary murine myotubes, TNFα suppresses Hsd11b1 mRNA expression and activity through the utilization of the alternative P1 promoter. As with MSCs, in response to TNFα treatment, NF-κB p65 was translocated to the nucleus. However, ChIP analysis demonstrated that the direct binding was seen at position −218 to −245 bp of the Hsd11b1 gene's P1 promoter but not at the P2 promoter. These studies demonstrate the existence of differential regulation of 11β-HSD1 expression in muscle cells through TNFα/p65 signalling and the P1 promoter, further enhancing our understanding of the role of 11β-HSD1 in the context of inflammatory disease.
format Online
Article
Text
id pubmed-4027025
institution National Center for Biotechnology Information
language English
publishDate 2014
publisher BioScientifica
record_format MEDLINE/PubMed
spelling pubmed-40270252014-05-22 TNFα-mediated Hsd11b1 binding of NF-κB p65 is associated with suppression of 11β-HSD1 in muscle Doig, Craig L Bashir, Jamila Zielinska, Agnieszka E Cooper, Mark S Stewart, Paul M Lavery, Gareth G J Endocrinol Research The activity of the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which converts inactive cortisone (11-dehydrocorticosterone (11-DHC)) (in mice) into the active glucocorticoid (GC) cortisol (corticosterone in mice), can amplify tissue GC exposure. Elevated TNFα is a common feature in a range of inflammatory disorders and is detrimental to muscle function in diseases such as rheumatoid arthritis and chronic obstructive pulmonary disease. We have previously demonstrated that 11β-HSD1 activity is increased in the mesenchymal stromal cells (MSCs) by TNFα treatment and suggested that this is an autoregulatory anti-inflammatory mechanism. This upregulation was mediated by the P2 promoter of the Hsd11b1 gene and was dependent on the NF-κB signalling pathway. In this study, we show that in contrast to MSCs, in differentiated C2C12 and primary murine myotubes, TNFα suppresses Hsd11b1 mRNA expression and activity through the utilization of the alternative P1 promoter. As with MSCs, in response to TNFα treatment, NF-κB p65 was translocated to the nucleus. However, ChIP analysis demonstrated that the direct binding was seen at position −218 to −245 bp of the Hsd11b1 gene's P1 promoter but not at the P2 promoter. These studies demonstrate the existence of differential regulation of 11β-HSD1 expression in muscle cells through TNFα/p65 signalling and the P1 promoter, further enhancing our understanding of the role of 11β-HSD1 in the context of inflammatory disease. BioScientifica 2014-03 /pmc/articles/PMC4027025/ /pubmed/24413279 http://dx.doi.org/10.1530/JOE-13-0494 Text en © 2014 The authors http://creativecommons.org/licenses/by/3.0/deed.en_GB This work is licensed under a Creative Commons Attribution 3.0 Unported License (http://creativecommons.org/licenses/by/3.0/deed.en_GB)
spellingShingle Research
Doig, Craig L
Bashir, Jamila
Zielinska, Agnieszka E
Cooper, Mark S
Stewart, Paul M
Lavery, Gareth G
TNFα-mediated Hsd11b1 binding of NF-κB p65 is associated with suppression of 11β-HSD1 in muscle
title TNFα-mediated Hsd11b1 binding of NF-κB p65 is associated with suppression of 11β-HSD1 in muscle
title_full TNFα-mediated Hsd11b1 binding of NF-κB p65 is associated with suppression of 11β-HSD1 in muscle
title_fullStr TNFα-mediated Hsd11b1 binding of NF-κB p65 is associated with suppression of 11β-HSD1 in muscle
title_full_unstemmed TNFα-mediated Hsd11b1 binding of NF-κB p65 is associated with suppression of 11β-HSD1 in muscle
title_short TNFα-mediated Hsd11b1 binding of NF-κB p65 is associated with suppression of 11β-HSD1 in muscle
title_sort tnfα-mediated hsd11b1 binding of nf-κb p65 is associated with suppression of 11β-hsd1 in muscle
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4027025/
https://www.ncbi.nlm.nih.gov/pubmed/24413279
http://dx.doi.org/10.1530/JOE-13-0494
work_keys_str_mv AT doigcraigl tnfamediatedhsd11b1bindingofnfkbp65isassociatedwithsuppressionof11bhsd1inmuscle
AT bashirjamila tnfamediatedhsd11b1bindingofnfkbp65isassociatedwithsuppressionof11bhsd1inmuscle
AT zielinskaagnieszkae tnfamediatedhsd11b1bindingofnfkbp65isassociatedwithsuppressionof11bhsd1inmuscle
AT coopermarks tnfamediatedhsd11b1bindingofnfkbp65isassociatedwithsuppressionof11bhsd1inmuscle
AT stewartpaulm tnfamediatedhsd11b1bindingofnfkbp65isassociatedwithsuppressionof11bhsd1inmuscle
AT laverygarethg tnfamediatedhsd11b1bindingofnfkbp65isassociatedwithsuppressionof11bhsd1inmuscle