TNF-alpha enhances intracellular glucocorticoid availability.
For understanding the mechanism(s) relating inflammation to corticosteroid action, the effect of tumour necrosis factor-alpha (TNF-alpha) on 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), the enzyme regulating access of 11beta-hydroxycorticosteroids to receptors, was studied in LLC-PK(1) cells. We observed (i) NAD-dependent enzyme activity and mRNA for 11beta-HSD2, but not 11beta-HSD1, (ii) increasing 11beta-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 11beta-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 11beta-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 11beta-HSD2 activity. In conclusion, TNF-alpha decreases 11beta-HSD2 activity and thereby enhances glucocorticoid access to glucocorticoid receptors to modulate the inflammatory response.
Heiniger
C D
CD
Division of Nephrology and Hypertension, Department of Internal Medicine, University Hospital of Berne, Freiburgstrasse 15, 3010, Berne, Switzerland.
Rochat
M K
MK
Frey
F J
FJ
Frey
B M
BM
D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D000818:Animals; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D003345:Corticosterone / Q000378:metabolism / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D015536:Down-Regulation; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005938:Glucocorticoids / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D006913:Hydroxysteroid Dehydrogenases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology
D004791:Enzyme Inhibitors; D005419:Flavonoids; D005938:Glucocorticoids; D007093:Imidazoles; D007211:Indoles; D008301:Maleimides; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D005576:Colforsin; D006913:Hydroxysteroid Dehydrogenases; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D017868:Cyclic AMP-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D005947:Glucose; C070515:bisindolylmaleimide I; D013755:Tetradecanoylphorbol Acetate; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D003345:Corticosterone