GLUCOCORTICOID-RECEPTORS AND MINERALOCORTICOID RECEPTORS IN MICROGLIAL CELLS - THE 2 RECEPTORS MEDIATE DIFFERENTIAL-EFFECTS OF CORTICOSTEROIDS

Effects of steroid hormones on the regulation of function and morpholo gy of microglial cells were investigated using the cultured cells :iso lated from forebrain of newborn rats. Cortisol, corticosterone, and al dosterone at 100 nM caused a strong shrinkage of microglial cells cult ured in a serum-supplemented medium. However, cholesterol, pregnenolon e, testosterone, estradiol, and dehydroepiandrosterone did not exhibit any significant effects. The corticosteroids also inhibited the GM-CS F-mediated ramification of microglia in a serum-free medium. An anti-g lucocorticoid agent RU38486 abolished the effects of corticosteroids o n the microglial morphology, suggesting the presence of functional glu cocorticoid receptor (GR) in microglial cells. The presence of GR was confirmed by immunoblotting with an antibody to the receptor. Cytokine s GM-CSF and interleukin-3 altered the level of GR expression, Binding experiments with [H-3]-corticosterone demonstrated the presence of no t only GR but also mineralocorticoid receptor (MR): the dissociation c onstants (Kd) and the number of binding sites (Bmax) were 0.8 nM and 1 5 fmol/mg protein for MR and 5.0 nM and 73 fmol/mg protein for GR, res pectively. The pure glucocorticoid RU28362 and dexamethasone at 20 nM (but not aldosterone and corticosterone at the same concentration) inh ibited proliferation of microglial cells, as revealed by PCNA immunocy tochemistry. RU28362 inhibited the activities of inducible nitric oxid e synthase and acid phosphatase at concentrations higher than 1 nM. Al dosterone and corticosterone exhibited the similar inhibitory effect a t 100 nM, and this inhibition was completely overcome by RU38486, On t he other hand, corticosterone and aldosterone at concentrations lower than 1 nM enhanced the activities of both enzymes, The antimineralocor ticoid agent spironolactone eliminated the stimulatory effects of cort icosterone on the enzyme activities, In accordance with these biochemi cal results, electron microscopic observations revealed that glucocort icoids enhanced the formation of lysosomal vacuolation in microglial c ells and aldosterone increased the number and size of lysosomes. In co nclusion, it is suggested that GR and MR mediated the opposite effects of corticosterone on the functions of microglial cells; the hormone a cted as an inhibitor through GR and as an stimulator through MR. (C) 1 997 Wiley-Liss, Inc.