Potencies of topical glucocorticoids to mediate genomic and nongenomic effects on human peripheral blood mononuclear cells.
Several different genomic and nongenomic mechanisms are known to mediate the important anti-inflammatory and immunomodulatory effects of glucocorticoids (GC). Genomic effects are the most important while the clinical relevance of nongenomic actions is still a matter of debate. We therefore investigated whether beclometasone and clobetasol are particularly suitable for topical application because of their specific spectrum of genomic and nongenomic actions. For these purposes we compared effects on oxygen consumption as measured with a Clark electrode (nonspecific nongenomic glucocorticoid effects), on interleukin-6 synthesis by means of ELISA (genomic effects) and on apoptosis using flow cytometry (nongenomic and genomic effects) in quiescent and mitogen-stimulated PBMC. Beclometasone and clobetasol indeed had stronger effects on the oxygen consumption of quiescent and stimulated cells at lower concentrations (10(-10) and 10(-8) M) but were less potent at higher concentrations (10(-5) and 10(-4) M) in comparison with dexamethasone. Also in terms of genomic potency, topical GC were more effective than dexamethasone at 10(-10) and 10(-8) M but gave similar results at higher concentrations. The ability of all three GC to induce apoptosis was found to be concentration-dependent and similar at concentrations between 10(-8) and 10(-5) M. But, compared with 10(-4) M dexamethasone, topical GC at 10(-4) M were significantly more effective at inducing apoptosis in both PBMC and Jurkat T-cells. These results show that topical GC have different concentration--(genomic/nongenomic) effect--ratios compared with dexamethasone: besides to the well-known genomic effects there are also significant nongenomic effects of topical glucocorticoids that already at low concentrations might be more therapeutically relevant in certain clinical conditions than currently assumed.
Naumann
Lydia
L
Department of Medicine (Rheumatology and Clinical Immunology), Charité University Hospital, Schumannstrasse 20/21, 10117 Berlin, Germany. lydia.naumann@charite.de
Feist
Eugen
E
Straub
Rainer H
RH
Burmester
Gerd-Rüdiger
GR
Buttgereit
Frank
F
D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001507:Beclomethasone / Q000494:pharmacology; D002990:Clobetasol / Q000494:pharmacology; D003208:Concanavalin A / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D019169:Jurkat Cells; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D010835:Phytohemagglutinins / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D015850:Interleukin-6; D010835:Phytohemagglutinins; D003208:Concanavalin A; D003907:Dexamethasone; D002990:Clobetasol; D001507:Beclomethasone