TNF-α enhances intracellular glucocorticoid availability

AbstractFor understanding the mechanism(s) relating inflammation to corticosteroid action, the effect of tumour necrosis factor-α (TNF-α) on 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), the enzyme regulating access of 11β-hydroxycorticosteroids to receptors, was studied in LLC-PK1 cells. We observed (i) NAD-dependent enzyme activity and mRNA for 11β-HSD2, but not 11β-HSD1, (ii) increasing 11β-HSD2 activity with increasing degree of differentiation and (iii) a concentration-dependent down-regulation by TNF-α, phorbol myristate acetate (PMA) or glucose of activity and mRNA of 11β-HSD2. The decrease of activity and mRNA by glucose and PMA, but not that by TNF-α, was abrogated by the protein kinase C inhibitor GF-109203X. The effect of TNF-α on 11β-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 11β-HSD2 activity. In conclusion, TNF-α decreases 11β-HSD2 activity and thereby enhances glucocorticoid access to glucocorticoid receptors to modulate the inflammatory response