Tumor necrosis factor alpha and interleukin 1 beta enhance the cortisone/cortisol shuttle

Endogenously released or exogenously administered glucocorticosteroids are relevant hormones for controlling inflammation. Only (11)beta-hydroxy glucocorticosteroids, but not Il-keto glucocorticosteroids, activate glucocorticoid receptors. Since we found that glomerular mesangial cells (GMC) express 11 beta-hydroxysteroid dehydrogenase 1 (11 beta-OHSD1), which interconverts Il-keto glucocorticosteroids into 11 beta-hydroxy glucocorticosteroids (cortisone/cortisol shuttle), we explored whether 11 beta-OHSD1 determines the antiinflammatory effect of glucocorticosteroids. GMC exposed to interleukin (IL)-1 beta or tumor necrosis factor alpha (TNF-alpha) release group II phospholipase A2 (PLA2), a key enzyme producing inflammatory mediators. 11 beta-hydroxy glucocorticosteroids inhibited cytokine-induced transcription and release of PLA2 through a glucocorticoid receptor-dependent mechanism. This inhibition was enhanced by inhibiting 11 beta-OHSD1. Interestingly, Il-keto glucocorticosteroids decreased cytokine-induced PLA2 release as well, a finding abrogated by inhibiting 11 beta-OHSD1. Stimulating GMC with IL-1 beta or TNF-alpha increased expression and reductase activity of 11 beta-OHSD1. Similarly, this IL-1 beta- and TNF-alpha-induced formation of active 11 beta-hydroxy glucocorticosteroids from inert Il-keto glucocorticosteroids by the 11 beta-OHSD1 was shown in the Kiki cell line that expresses the stably transfected bacterial beta-galactosidase gene under the control of a glucocorticosteroids response element. Thus, we conclude that 11 beta-OHSD1 controls access of 11 beta-hydroxy glucocorticosteroids and Il-keto glucocorticosteroids to glucocorticoid receptors and thus determines the anti-inflammatory effect of glucocorticosteroids. IL-1 beta and TNF-alpha upregulate specifically the reductase activity of 11 beta-OHSD1 and counterbalance by that mechanism their own proinflammatory effect.