Doig, CL, Bashir, J, Zielinska, AE et al. (3 more authors) (2014) TNFα-mediated Hsd11b1 binding of NF-κB p65 is associated with suppression of 11β-HSD1 in muscle. Journal of Endocrinology, 220 (3). 389 - 396. ISSN 0022-0795
Abstract
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 Hsd11β1 gene and was dependent on the NF-kB signalling pathway. In this study, we show that in contrast to MSCs, in differentiated C2C12 and primary murine myotubes, TNFα suppresses Hsd11β1 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 positionK218 toK245 bp of the Hsd11β1 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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | (c) 2014, Doig, CL, Bashir, J, Zielinska, AE, Cooper, MS, Stewart, PM and Lavery, GG. This is an Open Access article distributed in accordance with the Creative Commons Attribution (CC BY 3.0) licence, which permits others to distribute, remix, adapt, build upon this work, and license their derivative works on different terms, provided the original work is properly cited. |
Keywords: | Glucocorticoid; Inflammation; Metabolism; Muscle |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > Medicine & Health Faculty Office (Leeds) > Faculty Office Functions (FOMH) (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 04 Nov 2014 11:32 |
Last Modified: | 05 Nov 2014 10:43 |
Published Version: | http://dx.doi.org/10.1530/JOE-13-0494 |
Status: | Published |
Publisher: | BioScientifica |
Identification Number: | 10.1530/JOE-13-0494 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:81070 |