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TNF‐α enhances intracellular glucocorticoid availability
Author(s) -
Heiniger Christian D.,
Rochat Mascha K.,
Frey Felix J.,
Frey Brigitte M.
Publication year - 2001
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/s0014-5793(01)03004-6
Subject(s) - glucocorticoid , forskolin , endocrinology , medicine , kinase , tumor necrosis factor alpha , protein kinase a , activator (genetics) , mapk/erk pathway , p38 mitogen activated protein kinases , glucocorticoid receptor , chemistry , protein kinase c , receptor , phorbol , intracellular , biology , biochemistry
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‐PK 1 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.