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TNFα-mediated Hsd11b1 binding of NF-κB p65 is associated with suppression of 11β-HSD1 in muscle
- Source :
- The Journal of Endocrinology
- Publication Year :
- 2014
- Publisher :
- Bioscientifica, 2014.
-
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 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.
- Subjects :
- medicine.medical_specialty
muscle
Endocrinology, Diabetes and Metabolism
Muscle Fibers, Skeletal
Down-Regulation
Inflammation
Biology
Gene Expression Regulation, Enzymologic
Mice
Endocrinology
Downregulation and upregulation
Internal medicine
11-beta-Hydroxysteroid Dehydrogenase Type 1
medicine
Animals
Myocyte
Muscle, Skeletal
Promoter Regions, Genetic
Cell Nucleus
Tumor Necrosis Factor-alpha
Myogenesis
Research
Mesenchymal stem cell
Transcription Factor RelA
3. Good health
Protein Transport
inflammation
glucocorticoid
Tumor necrosis factor alpha
medicine.symptom
Signal transduction
metabolism
hormones, hormone substitutes, and hormone antagonists
Glucocorticoid
Protein Binding
Signal Transduction
medicine.drug
Subjects
Details
- ISSN :
- 14796805 and 00220795
- Volume :
- 220
- Database :
- OpenAIRE
- Journal :
- Journal of Endocrinology
- Accession number :
- edsair.doi.dedup.....4cc192397e93e6ef3a03d38ac2899044
- Full Text :
- https://doi.org/10.1530/joe-13-0494