TNF‐α enhances intracellular glucocorticoid availability

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Abstract
For 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.

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