11β-Hydroxysteroid dehydrogenase type 1 within muscle protects against the adverse effects of local inflammation.
11β-Hydroxysteroid dehydrogenase type 1 within muscle protects against the adverse effects of local inflammation.
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DOI：
10.1002/path.4806
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发表时间：
2016-12
影响因子：
7.3
通讯作者：
Raza, Karim
中科院分区：
文献类型：
--
作者：
Hardy, Rowan S.;Doig, Craig L.;Hussain, Zahrah;O'Leary, Mary;Morgan, Stuart A.;Pearson, Mark J.;Naylor, Amy;Jones, Simon W.;Filer, Andrew;Stewart, Paul M.;Buckley, Christopher D.;Lavery, Gareth G.;Cooper, Mark S.;Raza, Karim
肌肉萎缩是炎症性肌病的常见特征。糖皮质激素(GCs)虽然在抑制炎症和炎症性肌肉丢失方面有效，但长期服用也会导致肌病。11β-羟类固醇脱氢酶1(11β-HSD1)是一种双向GC激活酶，在间质来源的组织中可被炎症上调。我们评估了这种酶在肌肉炎症中的调节作用，并检查了它对肌肉功能的影响。在包括肌肉在内的组织中过表达肿瘤坏死因子-β的慢性炎症转基因小鼠模型中，检测了11个α-hsd1在促炎刺激下的表达。在原代培养的人和小鼠肌管以及人和小鼠肌肉活组织标本中检测了11个β-HSD1表达的炎症调节和功能后果。在11β-HSD1缺失的背景下，用肿瘤坏死因子-甘油三酯小鼠在体内评估了11β-HSD1对肌肉炎症和消瘦的贡献。11β-hsd1在胫前肌和股四头肌显著上调。在人和小鼠的原代肌管中，11个β-α的表达和活性在促炎细胞因子肿瘤坏死因子-hsd1的反应中显著增加(mRNA7.6倍，p<；0.005；活性，4.1倍，p<；0.005)。在人的肌管培养中，由11β-HSD1激活的生理水平的内源性GC抑制了促炎细胞因子的输出(白细胞介素6、肿瘤坏死因子-α和干扰素-γ)，但对肌肉萎缩的标志物几乎没有影响。与11β-11β-HSD1活性正常的肿瘤坏死因子-TG小鼠相比，11β-11 HSD1基因敲除背景下的肿瘤坏死因子-TG小鼠出现了更多的肌肉消耗(减少27.4%；p<；0.005)，肌肉纤维较小，致炎基因表达增加。这项研究表明，炎症刺激上调了肌肉中11个β-HSD1的表达和GC的激活。尽管GCs水平过高可能对肌肉有害，但在这个炎症性肿瘤坏死因子-α驱动的模型中，局部内源性GC激活似乎是一种重要的抗炎反应，可防止体内炎症性肌肉萎缩。©2016作者。《病理学杂志》由John Wiley&Sons Ltd代表大不列颠和爱尔兰病理学会出版。
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. 11β‐Hydroxysteroid dehydrogenase type 1 (11β‐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 11β‐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)‐α within tissues, including muscle. The inflammatory regulation and functional consequences of 11β‐HSD1 expression were examined in primary cultures of human and murine myotubes and human and murine muscle biopsies ex vivo. The contributions of 11β‐HSD1 to muscle inflammation and wasting were assessed in vivo with the TNF‐Tg mouse on an 11β‐HSD1 null background. 11β‐HSD1 was significantly upregulated within the tibialis anterior and quadriceps muscles from TNF‐Tg mice. In human and murine primary myotubes, 11β‐HSD1 expression and activity were significantly increased in response to the proinflammatory cytokine TNF‐α (mRNA, 7.6‐fold, p < 0.005; activity, 4.1‐fold, p < 0.005). Physiologically relevant levels of endogenous GCs activated by 11β‐HSD1 suppressed proinflammatory cytokine output (interkeukin‐6, TNF‐α, and interferon‐γ), but had little impact on markers of muscle wasting in human myotube cultures. TNF‐Tg mice on an 11β‐11β‐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 11β‐HSD1 activity. This study demonstrates that inflammatory stimuli upregulate 11β‐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‐α‐driven model, local endogenous GC activation appears to be an important anti‐inflammatory response that protects against inflammatory muscle wasting in vivo. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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影响因子：
4.1
作者：
Coutinho, Agnes E.;Chapman, Karen E.
通讯作者：
Chapman, Karen E.
影响因子：
4.9
作者：
Hardy, Rowan S.;Filer, Andrew;Hewison, Martin
通讯作者：
Hewison, Martin
影响因子：
3.4
作者：
ANGELINI, C;PEGORARO, E;COSTA, C
通讯作者：
COSTA, C
DOI：
10.1530/joe-16-0011
发表时间：
2016-06
期刊：
The Journal of endocrinology
影响因子：
--
作者：
Morgan SA;Hassan-Smith ZK;Doig CL;Sherlock M;Stewart PM;Lavery GG
通讯作者：
Lavery GG
影响因子：
11.4
作者：
KEFFER, J;PROBERT, L;KOLLIAS, G
通讯作者：
KOLLIAS, G