| First Author | Hardy RS | Year | 2016 |
| Journal | J Pathol | Volume | 240 |
| Issue | 4 | Pages | 472-483 |
| PubMed ID | 27578244 | Mgi Jnum | J:241737 |
| Mgi Id | MGI:5903564 | Doi | 10.1002/path.4806 |
| Citation | Hardy RS, et al. (2016) 11beta-Hydroxysteroid dehydrogenase type 1 within muscle protects against the adverse effects of local inflammation. J Pathol 240(4):472-483 |
| abstractText | Muscle wasting is a common feature of inflammatory myopathies. Glucocorticoids (GCs), although effective at suppressing inflammation and inflammatory muscle loss, also cause myopathy with prolonged administration. 11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) is a bidirectional GC-activating enzyme that is potently upregulated by inflammation within mesenchymal-derived tissues. We assessed the regulation of this enzyme with inflammation in muscle, and examined its functional impact on muscle. The expression of 11beta-HSD1 in response to proinflammatory stimuli was determined in a transgenic murine model of chronic inflammation (TNF-Tg) driven by overexpression of tumour necrosis factor (TNF)-alpha within tissues, including muscle. The inflammatory regulation and functional consequences of 11beta-HSD1 expression were examined in primary cultures of human and murine myotubes and human and murine muscle biopsies ex vivo. The contributions of 11beta-HSD1 to muscle inflammation and wasting were assessed in vivo with the TNF-Tg mouse on an 11beta-HSD1 null background. 11beta-HSD1 was significantly upregulated within the tibialis anterior and quadriceps muscles from TNF-Tg mice. In human and murine primary myotubes, 11beta-HSD1 expression and activity were significantly increased in response to the proinflammatory cytokine TNF-alpha (mRNA, 7.6-fold, p < 0.005; activity, 4.1-fold, p < 0.005). Physiologically relevant levels of endogenous GCs activated by 11beta-HSD1 suppressed proinflammatory cytokine output (interkeukin-6, TNF-alpha, and interferon-gamma), but had little impact on markers of muscle wasting in human myotube cultures. TNF-Tg mice on an 11beta-11beta-HSD1 knockout background developed greater muscle wasting than their TNF-Tg counterparts (27.4% less; p < 0.005), with smaller compacted muscle fibres and increased proinflammatory gene expression relative to TNF-Tg mice with normal 11beta-HSD1 activity. This study demonstrates that inflammatory stimuli upregulate 11beta-HSD1 expression and GC activation within muscle. Although concerns have been raised that excess levels of GCs may be detrimental to muscle, in this inflammatory TNF-alpha-driven model, local endogenous GC activation appears to be an important anti-inflammatory response that protects against inflammatory muscle wasting in vivo. (c) 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. |
