TNF-α enhances intracellular glucocorticoid availability

For understanding the mechanism(s) relating inflammation to corticosteroid action, the effect of tumour necrosis factor-alpha (TNF-alpha) on 11 beta -hydroxysteroid dehydrogenase type 2 (11 beta -HSD2), the enzyme regulating access of 11 beta -hydroxycorticosteroids to receptors, was studied in LLC-PK1 cells. We observed (i) NAD-dependent enzyme activity and mRNA for 11 beta -HSD2, but not 11 beta -HSD1, (ii) increasing 11 beta -HSD2, activity with increasing degree of differentiation and (iii) a concentration-dependent down-regulation by TNF-alpha, phorbol myristate acetate (PMA) or glucose of activity and mRNA of 11 beta -HSD2. The decrease of activity and mRNA by glucose and PMA, but not that by TNF-alpha, was abrogated by the protein kinase C inhibitor GF-109203X. The effect of TNF-alpha on 11 beta -HSD2 was reversed by inhibiting the mitogen-activated protein kinases ERK with PD-098050 and p38 by SB-202190, or by activating protein kinase A with forskolin. Overexpression of MEK1, an ERK activator, down-regulated the 11 beta -HSD2 activity. In conclusion, TNF-alpha decreases 11 beta -HSD2 activity and thereby enhances glucocorticoid access to glucocorticoid receptors to modulate the inflammatory response. (C) 2001 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved.