Background Local generation of endogenous glucocorticoids (GCs) by the enzyme 11beta-Hydroxysteroid Dehydrogenase Type 1 (11beta-HSD1) with inflammation has been shown to be an important anti-inflammatory pathway in both acute and chronic inflammatory disease. Whilst beneficial within inflamed tissues such as the rheumatoid synovium (through suppression of pro-inflammatory pathways), the inflammatory regulation and impact of 11beta-HSD1 on neighbouring tissues such as muscle remain poorly defined.
Objectives To characterise the inflammatory regulation of 11beta-HSD1 in muscle during systemic inflammation and examine its functional consequences on muscle inflammation and wasting in vitro and in vivo using primary human tissue and a transgenic murine model of polyarthritis.
Methods Inflammatory regulation of 11beta-HSD1 was examined in primary myotube culture and ex vivo muscle biopsies isolated from human donors and from transgenic TNF overexpressing (TNF-tg) mice, as a model of systemic polyarthritis. Inflammatory cytokine output, myotube viability and markers of inflammatory muscle wasting were measured following exposure to endogenous GCs activated by 11beta-HSD1. The contribution of 11beta-HSD1 to muscle status in vivo was examined in the TNF-tg mouse on an 11beta-HSD1 global null background.
Results In both human and murine primary muscle culture, 11beta-HSD1 mRNA and activity were significantly increased in response to the pro-inflammatory cytokine TNFa (mRNA; 7.6 fold, p<0.005, activity 4.1 fold, p<0.005). 11beta-HSD1 mRNA and activity were evident in ex vivo biopsies of murine and human muscle from tibialis anterior and quadriceps. This expression was augmented in response to TNFa and in muscles harvested from TNF-tg mice relative to wild type controls. Endogenous GCs activated by 11beta-HSD1 suppressed pro-inflammatory cytokine output of IL-6, TNFa, and IFNg, but had little impact on markers of muscle wasting and cell viability in myotube culture. To delineate the contribution of 11beta-HSD1 to suppression of inflammation and muscle wasting in vivo, we generated a TNF-tg mouse on an 11beta-HSD1KO background. These animals had more marked muscle wasting with reduced muscle weight relative to body weight (TNF-tg; 13.45%; TNF/11bKO, 36.2%; p<0.005), smaller compacted muscle fibres and increased pro-inflammatory gene expression.
Conclusions This study demonstrates that in muscle, as observed in tissues such as the rheumatoid synovium, 11beta-HSD1 and endogenous glucocorticoid activation are markedly increased in response to inflammation. Whilst concerns have been raised that excess levels of GCs may contribute to factors such as muscle wasting, in this model, local endogenous glucocorticoid activation appears to be overwhelmingly anti-inflammatory in nature and protective in regards to inflammatory muscle wasting in vivo.
Disclosure of Interest None declared