J. Exp. Med.
© The Rockefeller University Press
0022-1007/97/07/189/10 $2.00
Volume 186, Number 2, July 21, 1997 189-198

Tumor Necrosis Factor  and Interleukin 1 Enhance the Cortisone/Cortisol Shuttle

By Geneviève Escher, Ivo Galli, Bannikuppe S. Vishwanath, Brigitte M. Frey, and Felix J. Frey

From the Division of Nephrology, University Hospital of Berne, 3010 Berne, Switzerland

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

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