Suppression of thymus-dependent immune functions by glucocorticoids and presence of a sexual dimorphism in the immune response are two important characteristics. The aim of the present study was to identify the expression of the glucocorticoid receptor (GR) gene in the thymus and to determine alterations in GR messenger ribonucleic acid concentration during physiological or pharmacological alterations of the sex steroid hormone milieu, and/or after adrenalectomy and corticosterone replacement. Moreover, changes in GR transcript levels were correlated with thymocyte's cell-mediated immune response to phytomitogens and corticosterone under the different hormonal conditions studied. Using a 2.2 kb cRNA probe, we have identified an approximately 6.7 kb GR transcript in the thymus corresponding to that seen in the rat pituitary gland and liver tissues. Northern blot analysis revealed marked alterations of GR mRNA concentrations during the different phases of the rat estrous cycle characterized by a significant decrease in GR mRNA content measured on the day of maximal estrogenic stimulation, i.e. proestrous, and a highly significant increase of GR mRNA content on the day of estrous. Type II GR mRNA levels of pregnant rats were significantly reduced compared to GR transcript levels measured at estrous or diestrous. A further loss of type II GR signal was observed the first day of lactation, while GR mRNA concentration rose to levels measured in diestrous animals, during mid lactation. Four weeks after ovariectomy GR mRNA concentration was increased approximately three- to fourfold above the levels measured in sham-ovariectomized animals sacrificed on the day of diestrous 1 (D1), diestrous (D2), or proestrous. The effect of ovariectomy was maximal 12 days after surgery, and GR mRNA concentration remained elevated for at least up to 4 weeks. Daily treatment of ovariectomized animals with 17-beta-estradiol for 4 weeks completely reversed the OVX-induced increase in GR mRNA content of the thymus gland, while administration of progesterone failed to modify the elevated GR transcripts. The estrogen counteraction of OVX-induced rise in GR mRNA levels was already significant 1 day following the steroid administration, and GR mRNA content remained inhibited for the entire duration of estradiol treatment. Administration of corticosterone to intact rats reduced significantly GR mRNA concentration, but failed to influence the ovariectomy-induced increase in GR mRNA content. Adrenalectomy induced an up-regulation of GR mRNA levels. These increased transcript levels were down-regulated by corticosterone and dexamethazone. The combined manipulation (ADX + OVX) raised the GR mRNA concentrations to levels even higher than those found after ADX alone. When the ability of rat thymocytes to respond to the T-dependent mitogen, concanavalin A (Con-A, 2.5 mu g ml) in vitro, was tested under the different experimental conditions, a marked hormonal modulation of thymocyte's blastogenic potential was observed. Corticosterone treatment of thymocyte cell cultures produced a significant inhibition of T-cell proliferation, that was dependent upon the sex steroid hormone milieu. These results suggest that ovarian and adrenal hormones exert a profound modulatory effect on GR mRNA concentration in the rat thymus. The negative regulation of thymic GR mRNA by estrogens may represent an important mechanism by which sex steroid hormones modulate glucocorticoid action in the thymus.
|Titolo:||Modulation of glucocorticoid receptor gene expression in the thymus by the sex steroid hormone milieu and correlation with sexual dimorphism of immune response|
|Data di pubblicazione:||1994|
|Appare nelle tipologie:||1.1 Articolo in rivista|