Inhibition of skin 11beta-hydroxysteroid dehydrogenase activity in vivo potentiates the anti-inflammatory actions of glucocorticoids.
Synthetic forms of glucocorticoids (GCs) with high potency are widely used to treat a number of dermatological conditions having an inflammatory or autoimmune etiology. While GCs are generally effective in their ability to suppress inflammatory processes, their chronic use can lead to detrimental systemic side effects. In this report, we describe a method by which the localized antiinflammatory potential of the natural GC cortisol can be significantly augmented without increasing the risk of negative systemic effects. 11Beta-hydroxysteroid dehydrogenase (11beta-HSD) is a naturally occurring enzyme in the skin. 11Beta-HSD functionally converts biologically active 11-hydroxy GCs to their biologically inactive 11-keto metabolites, thereby limiting the ability of GCs to mediate antiinflammatory activities. By topically applying specific inhibitors of 11beta-HSD in conjunction with low doses of GCs, the antiinflammatory properties of cortisol can be significantly potentiated. It was observed that the generation of the effector phase of contact hypersensitivity (CH) responses could be suppressed by this combined treatment under conditions where the 11beta-HSD inhibitor alone, or cortisol alone were only minimally effective. Only the combined treatment was effective at inhibiting the progression of an ongoing CH response.
University of Utah School of Medicine, Department of Obstetrics and Gynecology, Salt Lake City 84132, USA.
J D
JD
Hennebold
R A
RA
Daynes
D042842:11-beta-Hydroxysteroid Dehydrogenases; D000287:Administration, Topical; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D003877:Dermatitis, Contact / Q000188:drug therapy / Q000201:enzymology; D004139:Dinitrofluorobenzene; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology* / Q000627:therapeutic use; D006034:Glycyrrhetinic Acid / Q000494:pharmacology / Q000627:therapeutic use; D006854:Hydrocortisone / Q000494:pharmacology / Q000627:therapeutic use; D006908:Hydroxyprogesterones / Q000494:pharmacology / Q000627:therapeutic use; D006913:Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D051379:Mice; D008809:Mice, Inbred C3H; D012867:Skin / Q000187:drug effects* / Q000201:enzymology* / Q000473:pathology
D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D006908:Hydroxyprogesterones; C030228:11-hydroxyprogesterone; D004139:Dinitrofluorobenzene; D006913:Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases; D006034:Glycyrrhetinic Acid; D006854:Hydrocortisone