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11?-Hydroxysteroid dehydrogenase type 1 within muscle protects against the adverse effects of local inflammation.

ABSTRACT: 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. 11?-Hydroxysteroid dehydrogenase type 1 (11?-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 11?-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)-? within tissues, including muscle. The inflammatory regulation and functional consequences of 11?-HSD1 expression were examined in primary cultures of human and murine myotubes and human and murine muscle biopsies ex vivo. The contributions of 11?-HSD1 to muscle inflammation and wasting were assessed in vivo with the TNF-Tg mouse on an 11?-HSD1 null background. 11?-HSD1 was significantly upregulated within the tibialis anterior and quadriceps muscles from TNF-Tg mice. In human and murine primary myotubes, 11?-HSD1 expression and activity were significantly increased in response to the proinflammatory cytokine TNF-? (mRNA, 7.6-fold, p < 0.005; activity, 4.1-fold, p < 0.005). Physiologically relevant levels of endogenous GCs activated by 11?-HSD1 suppressed proinflammatory cytokine output (interkeukin-6, TNF-?, and interferon-?), but had little impact on markers of muscle wasting in human myotube cultures. TNF-Tg mice on an 11?-11?-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 11?-HSD1 activity. This study demonstrates that inflammatory stimuli upregulate 11?-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-?-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.

SUBMITTER: Hardy RS

PROVIDER: S-EPMC5111591 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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11β-Hydroxysteroid dehydrogenase type 1 within muscle protects against the adverse effects of local inflammation.

Hardy Rowan S RS Doig Craig L CL Hussain Zahrah Z O'Leary Mary M Morgan Stuart A SA Pearson Mark J MJ Naylor Amy A Jones Simon W SW Filer Andrew A Stewart Paul M PM Buckley Christopher D CD Lavery Gareth G GG Cooper Mark S MS Raza Karim K

The Journal of pathology 20161018 4

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 muscl ...[more]

PMID: 27578244

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Project description:Chronically elevated glucocorticoid levels impair cognition and are pro-inflammatory in the brain. Deficiency or inhibition of 11β-hydroxysteroid dehydrogenase type-1 (11β-HSD1), which converts inactive into active glucocorticoids, protects against glucocorticoid-associated chronic stress- or age-related cognitive impairment. Here, we hypothesised that 11β-HSD1 deficiency attenuates the brain cytokine response to inflammation. Because inflammation is associated with altered energy metabolism, we also examined the effects of 11β-HSD1 deficiency upon hippocampal energy metabolism. Inflammation was induced in 11β-HSD1 deficient (Hsd11b1Del/Del) and C57BL/6 control mice by intraperitoneal injection of lipopolysaccharide (LPS). LPS reduced circulating neutrophil and monocyte numbers and increased plasma corticosterone levels equally in C57BL/6 and Hsd11b1Del/Del mice, suggesting a similar peripheral inflammatory response. However, the induction of pro-inflammatory cytokine mRNAs in the hippocampus was attenuated in Hsd11b1Del/Del mice. Principal component analysis of mRNA expression revealed a distinct metabolic response to LPS in hippocampus of Hsd11b1Del/Del mice. Expression of Pfkfb3 and Ldha, key contributors to the Warburg effect, showed greater induction in Hsd11b1Del/Del mice. Consistent with increased glycolytic flux, levels of 3-phosphoglyceraldehyde and dihydroxyacetone phosphate were reduced in hippocampus of LPS injected Hsd11b1Del/Del mice. Expression of Sdha and Sdhb, encoding subunits of succinate dehydrogenase/complex II that determines mitochondrial reserve respiratory capacity, was induced specifically in hippocampus of LPS injected Hsd11b1Del/Del mice, together with increased levels of its product, fumarate. These data suggest 11β-HSD1 deficiency attenuates the hippocampal pro-inflammatory response to LPS, associated with increased capacity for aerobic glycolysis and mitochondrial ATP generation. This may provide better metabolic support and be neuroprotective during systemic inflammation or aging.

Project description:BackgroundHuman bone marrow mesenchymal stem cell (MSC) administration reduces inflammation in pre-clinical models of sepsis and sepsis-related lung injury, however clinical efficacy in patients has not yet been demonstrated. We previously showed that Alveolar Macrophage (AM) 11β-hydroxysteroid dehydrogenase type-1 (HSD-1) autocrine signalling is impaired in critically ill sepsis patients, which promotes inflammatory injury. Administration of transgenic MSCs (tMSCs) which overexpress HSD-1 may enhance the anti-inflammatory effects of local glucocorticoids and be more effective at reducing inflammation in sepsis than cellular therapy alone.MethodsMSCs were transfected using a recombinant lentiviral vector containing the HSD-1 and GPF transgenes under the control of a tetracycline promoter. Thin layer chromatography assessed HSD-1 reductase activity in tMSCs. Mesenchymal stem cell phenotype was assessed by flow cytometry and bi-lineage differentiation. HSD-1 tMSCs were co-cultured with LPS-stimulated monocyte-derived macrophages (MDMs) from healthy volunteers prior to assessment of pro-inflammatory cytokine release. HSD-1 tMSCs were administered intravenously to mice undergoing caecal ligation and puncture (CLP).ResultsMSCs were transfected with an efficiency of 91.1%, and maintained an MSC phenotype. Functional HSD-1 activity was demonstrated in tMSCs, with predominant reductase cortisol activation (peak 8.23 pM/hour/100,000 cells). HSD-1 tMSC co-culture with LPS-stimulated MDMs suppressed TNFα and IL-6 release. Administration of transgene activated HSD-1 tMSCs in a murine model of CLP attenuated neutrophilic inflammation more effectively than transgene inactive tMSCs (medians 0.403 v 1.36 × 106/ml, p = 0.033).ConclusionThe synergistic impact of HSD-1 transgene expression and MSC therapy attenuated neutrophilic inflammation in a mouse model of peritoneal sepsis more effectively than MSC therapy alone. Future studies investigating the anti-inflammatory capacity of HSD-1 tMSCs in models of sepsis-related direct lung injury and inflammatory diseases are required.

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11?-Hydroxysteroid dehydrogenase type 1 within muscle protects against the adverse effects of local inflammation.

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11β-Hydroxysteroid dehydrogenase type 1 within muscle protects against the adverse effects of local inflammation.

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