Mechanisms and clinical relevance of nongenomic glucocorticoid actions

Journal/Book: Z Rheumatol 1999; 58: 307. 1999;

Abstract: F. Buttgereit; Medizinische Universitätsklinik und Poliklinik III Medizinische Fakultät (Charité) Berlin The dogma of genomic glucocorticoid action that involves intracellular receptors certainly has its fascinating facets. However despite early observations on rapid steroid effects and on qualitatively different beneficial therapeutic effects of high dose glucocorticoids being clearly incompatible with this theory only recently has nongenomic steroid action been more widely recognised and led to a critical reappraisal of unsolved questions about this dogma. Intravenous pulse therapy with glucocorticoids is as effective in acute situations of SLE and other autoimmune diseases as topical therapy is in skin lung or joint diseases. Therefore nongenomic mechanisms of glucocorticoid action in these clinical situations are being studied with regard to membrane receptors and physicochemical effects on membranes. Our objective was to prove the clinical relevance of these nongenomic effects on cellular energy metabolism. Therefore we measured the short term effects of high doses of Methylprednisolon (MP) on oxygen consumption calcium metabolism mitochondrial membrane potential and several different ATP-consuming pathways in quiescent and Con A-stimulated rat thymocytes. Clinically relevant MP concentrations inhibit plasma membrane Ca2+ und Na+ uptake RNA/DANN synthesis and substrate oxidation reactions and stimulates the leak of protons across the mitochondrial inner membrane. It abolishes the Ca2+ rise and the respiratory stimulation caused by Con A in a dose dependent manner whereas protein synthesis is relatively unaffected by MP. These effects are clearly nongenomic effects since they occur within seconds. They are either mediated by physicochemical effects on membrane properties and/or by fast responding membrane receptors. Since these effects in vitro are seen at concentrations that are experienced by cells of the immune system during pulse or topical therapy and would clearly have the effect of diminishing and preventing the acute immune response we conclude that they underlie the beneficial clinical effects of the drug in active autoimmune diseases and in topical therapy. ... le

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