Steroids decrease granulocyte membrane fluidity, while phorbol ester increases membrane fluidity. Studies using electron paramagnetic resonance.
High concentrations of corticosteroids inhibit granulocyte responses and disrupt agonist receptor function. Dose-response and time-course considerations make it unlikely that these effects are mediated via the glucocorticoid receptor, a concept further supported by the ability of sex steroids to work similar effects. We postulated that steroids nonspecifically altered granulocyte membrane fluidity, which we measured directly by electron paramagnetic resonance. As predicted, methylprednisolone caused a dose-dependent increase in order parameter (decrease in fluidity) calculated on the basis of EPR spectra, using 5-doxylstearic acid (5-DS) as a probe of resting PMN membranes. This trend was highly significant (P less than 0.001; P at 0.5 mg/ml less than 0.01). Qualitatively similar results (but with different dose-response features) were obtained with conjugated estrogen. Granulocyte agonists (such as PMA) showed an opposite effect, which was not oxidatively mediated and which was steroid-inhibitable. 16-DS showed less prominent effects, suggesting that the membrane leaflets were more strongly affected than was the deep region of the membrane. Ibuprofen, which has similar effects to those of methylprednisolone on PMN aggregation and receptor function, caused a fluidizing rather than a stiffening of the membrane; this surprising result may indicate that there is a critical range of membrane fluidity for normal function, outside of which--in either direction--agonist receptor dysfunction occurs. We conclude that the immediate effects of very high doses of steroids are probably not mediated by corticoid receptors; instead, they may be due to changes in membrane fluidity.
Lamche
H R
HR
Department of Internal Medicine, University of Minnesota Medical School, Minneapolis.
Silberstein
P T
PT
Knabe
A C
AC
Thomas
D D
DD
Jacob
H S
HS
Hammerschmidt
D E
DE
D004578:Electron Spin Resonance Spectroscopy; D004966:Estrogens, Conjugated (USP) / Q000494:pharmacology*; D006098:Granulocytes / Q000187:drug effects*; D006801:Humans; D007052:Ibuprofen / Q000494:pharmacology; D066298:In Vitro Techniques; D008560:Membrane Fluidity / Q000187:drug effects*; D008775:Methylprednisolone / Q000031:analogs & derivatives*; D008776:Methylprednisolone Hemisuccinate / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
D004966:Estrogens, Conjugated (USP); D008776:Methylprednisolone Hemisuccinate; D013755:Tetradecanoylphorbol Acetate; D007052:Ibuprofen; D008775:Methylprednisolone