TNFα-mediated Hsd11b1 binding of NF-κB p65 is associated with suppression of 11β-HSD1 in muscle

The activity of the enzyme 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-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 TNF alpha 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 11 beta-HSD1 activity is increased in the mesenchymal stromal cells (MSCs) by TNF alpha 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-kappa B signalling pathway. In this study, we show that in contrast to MSCs, in differentiated C2C12 and primary murine myotubes, TNF alpha suppresses Hsd11b1 mRNA expression and activity through the utilization of the alternative P1 promoter. As with MSCs, in response to TNF alpha treatment, NF-kappa B 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 11 beta-HSD1 expression in muscle cells through TNF alpha/p65 signalling and the P1 promoter, further enhancing our understanding of the role of 11 beta-HSD1 in the context of inflammatory disease.