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Biomedical subjects

R L Spencer

Publications and source records attributed to R L Spencer.

At least 19 recordsLinked to original sources
PubMed1995

Effects of stress on immune cell distribution. Dynamics and hormonal mechanisms.

Immune cell trafficking is crucial to the performance of the surveillance as well as effector functions of the immune system. Because immune cells travel between tissues through the bloodstream, the numbers and proportions of leukocytes in the circulation provide an important representation of the state of leukocyte distribution in the body. The studies described here examine significant and selective changes in numbers and percentages of peripheral blood leukocyte subpopulations in the rat. These changes were rapidly induced under conditions of mild acute stress. Stress-induced increases in plasma corticosterone were accompanied by a significant decrease in numbers and percentages of lymphocytes, and by an increase in numbers and percentages of neutrophils. flow cytometric analysis revealed that B cell, NK cell, and monocyte numbers showed a greater stress-induced decrease than did T cells. All stress-induced changes were observed during the light (inactive) as well as the dark (active) period of the animal's diurnal cycle. Importantly, the stress-induced changes in leukocyte numbers and percentages were rapidly reversed upon the cessation of stress. Furthermore, the effects of stress were largely dependent on adrenal hormones, because the magnitude of the stress-induced changes was significantly reduced in adrenalectomized animals. Moreover, administration of corticosterone to adrenalectomized animals resulted in a close replication of stress-induced changes observed in adrenal-intact animals. These results suggest that endocrine factors released during stress modulate leukocyte trafficking and result in the redistribution of leukocytes between the blood and other immune compartments. Such a redistribution may significantly affect the ability of the immune system to respond to potential or ongoing immune challenge.

Adrenal Glands↗
PubMed1995

Mechanism of interleukin 12-mediated toxicities during experimental viral infections: role of tumor necrosis factor and glucocorticoids.

Interleukin 12 (IL-12) doses in excess of 100 ng/d have been shown to induce profound immunotoxicities in mice infected with lymphocytic choriomeningitis virus (LCMV). These immunotoxicities are characterized by almost complete inhibition of virus-induced CD8+ T cell expansion and CTL activation, and up to 2 log increases in viral replication. They are accompanied by induction of serum tumor necrosis factor (TNF). The studies presented here were undertaken to characterize mechanisms for the IL-12-induced toxicities and to examine expression and function of TNF in this context. Several physiological changes were induced in IL-12-treated uninfected and dramatically elevated in IL-12-treated virus-infected mice. IL-12 induced (a) decreases in body weights, > 10% in uninfected and > 20% in LCMV-infected mice; (b) elevation of circulating glucocorticoid levels to > 10 micrograms/dl in uninfected and > 20 micrograms/dl in infected mice; and (c) decreases in thymic mass, > 30% in uninfected and up to 95% in infected mice. These changes are known to be associated with circulating TNF. Northern blot and in situ hybridization analyses demonstrated that IL-12 induced TNF-alpha expression and that LCMV infection synergized with IL-12 for induction of this factor. Antibodies neutralizing TNF reversed all of the IL-12-induced toxicities in LCMV-infected mice including the immunotoxicities against CD8+ T cells and anti-viral defenses. The TNF-mediated immunotoxicities appeared to result from an induced cellular sensitivity to the factor, as splenic leukocytes and CD8+ T cell subsets isolated from LCMV-infected mice were more sensitive to TNF-mediated cytotoxicity in culture than were equivalent populations prepared from uninfected mice. Experiments with the glucocorticoid type II receptor antagonist, RU486, demonstrated that endogenous glucocorticoids were secondary intermediaries in IL-12-induced thymic atrophy. Studies in IL-2-deficient mice showed that the synergism was dependent upon endogenous IL-2. The results delineate a unique mechanism of TNF-mediated toxicity. In addition, they have significant implications concerning potential detrimental consequences of in vivo TNF induction and of IL-12 administration for protective anti-viral responses.

Animals↗
PubMed1995

Differential activation of adrenal steroid receptors in neural and immune tissues of Sprague Dawley, Fischer 344, and Lewis rats.

Sprague Dawley (SD), Fischer 344 (F344), and Lewis (LEW) rats are used in a wide variety of laboratory studies. Compared to SD and LEW rats, F344 rats show significantly greater corticosterone secretion in response to stress, or to immune challenge. These strain differences in hypothalamic-pituitary-adrenal (HPA) axis responsivity have been the basis for many comparative studies investigating immunological and behavioural differences between the three strains. However, the effects of these strain differences in HPA axis responsivity have not been investigated at the level of adrenal steroid receptor activation in target tissues. The present study demonstrates that compared to SD and LEW rats, F344 rats exhibited a greater magnitude of Type II adrenal steroid receptor activation in brain tissues during stress. In contrast, Type II receptor activation in immune tissues of F344 rats following stress was similar to that of SD rats. Importantly, LEW rats exhibited the lowest magnitude of activation of Type II receptors in immune tissues during stress. No differences were observed between strains in the extent of stress-induced Type I adrenal steroid receptor activation. The observed differences between strains in corticosteroid-binding globulin (CBG) levels in plasma, pituitary, and immune tissue may mediate the differential access of corticosterone to neural versus immune tissues. These results indicate that strain differences in corticosterone secretion are manifested by differences in Type II receptor activation in neural as well as immune tissues. Moreover, they suggest that increased access of corticosterone to adrenal steroid receptors in brain areas of F344 rats may contribute to behavioural differences between strains, whereas decreased access of hormone to receptors in immune tissues of LEW rats may contribute to strain differences in susceptibility to autoimmune disease.

Adrenal Glands↗
PubMed1995

Water maze performance of aged Sprague-Dawley rats in relation to retinal morphologic measures.

The spatial learning ability of aged male and female Sprague-Dawley rats was assessed using the Morris water maze. To determine the influence of age-related visual deficits on performance levels, retinal morphologic measures were correlated with water maze performance for each rat. Rats were first trained on the water maze task at 21 months of age and were retrained 3 or 4 times at 6-week intervals. After the last training session the rats were killed and their eyes were removed for histopathologic and morphometric evaluation of the retinas. There was a large degree of retinal degeneration in all of the aged Sprague-Dawley rats with an average decrease in the thickness of the retinal outer nuclear layer (photoreceptor nuclei containing layer) of 85% in old males and 95% in old females. Some rats, however, had less degeneration of the retinas than others, and the degree of retinal degeneration was strongly related to performance levels on the water maze task. Among the aged rats in this study with the least retinal degeneration, there was little evidence for a subset of rats that were unable, with extensive training, to learn a platform position. Of the 41 rats with the least retinal degeneration (out of a total of 81), only one was a clear non-learner on the water maze task, whereas, of the 27 rats with the most retinal degeneration, 20 were non-learners. These results illustrate the potentially serious confounding effects of deteriorating visual ability on attempts to assess cognitive functioning of aged albino rats on tasks requiring utilization of visual cues.

Aging↗
PubMed1995

Analysis of severe photoreceptor loss and Morris water-maze performance in aged rats.

In a study of aging and memory in 25-27-month-old albino rats, performance on a Morris water maze was found to be dependent on the structural integrity of the retina. Generally, as expected, 'learners' had intact retinas, while 'non-learners' had retinas with severe photoreceptor loss and a non-continuous outer nuclear layer, consisting of scattered cell nuclei. However, contrary to this general correlation between learning ability and photoreceptor presence, some learners had severely degenerated retinas and occasionally, non-learners had photoreceptor populations that apparently were comparable to those of learners. Rat retinas from these unpredictable, borderline response categories were examined histopathologically and morphometrically with the purpose of determining the minimal number of photoreceptors (PRs) necessary for animals to be rated as learners on the Morris water maze. However, among these severely damaged retinas of borderline groups, total number of surviving photoreceptors did not vary significantly among the learner, ambiguous or marginal and non-learner groups. The population of surviving PRs in learners was as low as 0.04% and in non-learners as high as 0.4%, as compared to that of young, adult rats. Therefore, borderline learners and non-learners had overlapping surviving PR numbers and the results did not clarify the response difference between these groups in the Morris water maze. It is suggested that the pattern of surviving PRs over the retinal surface, as well as the ratio of surviving rods to cones and their connectivity with other retinal neurons, may be related to the residual function of degenerated retinas of learner rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1995

Visible burrow system as a model of chronic social stress: behavioral and neuroendocrine correlates.

In mixed-sex rat groups maintained in visible burrow systems (VBS), consistent asymmetries in offensive and defensive behaviors of male dyads are associated with the development of dominance hierarchies. Subordinate males are characterized by particular wound patterns, severe weight loss, and a variety of behavioral changes, many of them isomorphic to target symptoms of clinical depression. In two VBS studies, subordinate males showed increased basal levels of plasma corticosterone (CORT), and increased adjusted adrenal and spleen weights compared to controls, and often, to dominants as well. Thymus weights and testosterone levels of subordinates were not reliably different in one study using highly aggressive males, but were reduced, along with testes weights, in a second study using unselected males. Glucocorticoid receptor binding levels in hippocampus, hypothalamus, and pituitary were not different, nor were aldosterone levels. When tested in a restraint stress procedure, subordinates had higher basal CORT levels, but about 40% of these animals showed a reduced, or absent, CORT response to restraint. These findings indicate that subordination may be reflected in high magnitude changes consistent with physiological indices of prolonged stress. Dominant rats of such groups may also show physiological changes suggesting stress, particularly when the groups are comprised of highly aggressive males only. The VBS colony model thus appears to enable rat groups to produce natural, stress-engendering, social interactions that constitute a particularly relevant model for investigating the behavioral, neural, and endocrine correlates of chronic stress.

Adrenal Glands↗
PubMed1995

A long-term increase in basal levels of corticosterone and a decrease in corticosteroid-binding globulin after acute stressor exposure.

Adrenal glucocorticoids play an important role in mediating many of the behavioral and physiological effects of exposure to stressors. Focus has been primarily on the acute stress-induced rise in glucocorticoids [corticosterone (CORT) in the rat]. There are reports, however, that exposure to chronic stressors can produce an increase in basal CORT and a decrease in corticotropin-binding globulin (CBG). These changes occur subsequent to the stress-induced rise in CORT. The following experiments examined whether exposure to an acute stressor (100 5-sec inescapable tail shocks; IS) could also produce long term changes in basal CORT and CBG. We report that a single session of IS results in an increase in basal total serum CORT that persists 48-96 h after IS termination. The increase is present only at the diurnal trough (morning). CBG levels ae also decreased for 24-48 h. The decrease is present at both the diurnal peak (evening) as well as the trough (morning). These changes result in an increase in the percent and amount of biologically active CORT (unbound or free). Thus, glucocorticoid-sensitive targets are exposed to high levels of free CORT for several days after IS termination. The long term increase in free CORT reported here may play an important role in mediating some of the effects produced by IS as well as those produced by other acute stressors.

Animals↗
PubMed1994

Cytosolic phospholipase C activity: I. Evidence for coupling with cytosolic guanine nucleotide-binding protein, Gi alpha.

In a previous report we showed that glucocorticoid inhibition of cytosolic PLC activity correlated with a reduction in cytosolic Gi alpha levels, suggesting that there may be a functional relationship between cytosolic PLC and cytosolic Gi alpha. In order to establish the nature of the coupling between cytosolic Gi alpha and cytosolic PLC we examined the effects of G-protein activators, and inhibitors on cytosolic PLC activity from rat splenocytes and the rat lymphoma cell line Nb 2, with [3H] PI and [3H]PIP2 as substrates. 1) Neither GTP nor its nonhydrolyzable analogue, GTP gamma S, at 100 microM had any effect on the calcium stimulated as well as the basal PLC activity. 2) However, affinity purified antibodies to Gi alpha 1 and Gi alpha 2 inhibited soluble PLC activity, by 85% and 55%, respectively, with PI as substrate; with PIP2 as substrate, soluble PLC activity was inhibited 50-70% by antibodies to Gi1, whereas antibodies to Gi2 had little effect. 3) Administration of Gi alpha 1 antisense oligonucleotides to splenocytes for 48 h produced 25-40% decrease in cytosolic Gi alpha 1 levels compared to control. The soluble PLC activity with both PI and PIP2 as substrates was also reduced by 25-50% compared to control conditions. This suggest that cytosolic Gi alpha is associated with the activation of splenocyte soluble PLC. 4) Pertussis toxin administered in vivo significantly reduced cytosolic Gi alpha immunoreactivity and soluble PLC activity when PI was used as substrate, providing additional evidence that cytosolic Gi alpha is associated with the activation of soluble PLC. 5) Another agent that has been used extensively to define G-protein coupled processes is NaF/AlCl3. NaF (5 mM; with or without AlCl3) inhibited soluble PLC activity with PIP2 as substrate, in contrast to the stimulatory effect that has been reported in the activation of membrane PLC. 6) Because NaF can act as a protein phosphatase inhibitor, we also tested the effects of trifluoperizine (50 microM, TFP), an inhibitor of protein phosphatase 2B; TFP (50 microM) significantly inhibited soluble PLC activity when PI was used as substrate. These results suggest a direct involvement of cytosolic Gi alpha in the activation of soluble PLC from splenocytes. Other questions pertaining to the functional significance, the nature, and possible substrate preference of the splenocyte Gi alpha coupled PLC is addressed in the second paper.

Animals↗
PubMed1994

Cytosolic phospholipase C activity: II. Relationship to concanavalin A-induced phosphatidylinositol-turnover in splenocytes.

We have described in the first paper the coupling between cytosolic Gi alpha and cytosolic PLC activity in a cell free preparation. In order to establish the functional significance of the cytosolic Gi alpha coupled soluble PLC, we examined the effects of DEX, NaF, and trifluoperizine (TFP) on concanavalin A (Con A)-induced PI-turnover in intact splenocytes and, in parallel, on soluble PLC activity in cytosol preparations. Cytosolic PLC activity was measured with [3H]PI and [3H]PIP2 as substrates. 1) The Con A-induced increase (2-4 fold) in PI-turnover in intact splenocytes was paralleled by an 1.2-5-fold increase in soluble PLC activity in vitro. Con A administration also increased cytosolic Gi alpha immunoreactivity 3-6-fold as expected if cytosolic Gi alpha was coupled to soluble PLC activation. 2) DEX (10(-7) M), administered 6 h prior to Con A administration, inhibited the Con A-induced increase in PI-turnover in intact splenocytes. This was paralleled by DEX inhibition of the Con A-induced increase in soluble PLC activity measured in vitro and cytosolic Gi alpha immunoreactivity. 3) We have demonstrated in the first paper that NaF and TFP inhibited soluble PLC activity. Here we show that NaF and TFP inhibited the Con A-induced increase in PI-turnover extending the similarities between soluble PLC activity and Con A-stimulated PLC activity in intact splenocytes. 4) In order to examine whether or not the Con A-induced PLC was similar to PLC gamma, we measured PI-turnover induced by Con A or NaVO3 in combination with DEX and PMA. Whereas the Con A-induced PI-turnover was significantly inhibited (40-60%) by DEX, the NaVO3-induced PI-turnover was not affected by DEX. The Con A-induced PI-turnover was not affected by PMA (50 nM), but the NaVO3-induced PI-turnover was increased over 2-fold by PMA (50 nM), suggesting that the Con A-induced PLC in intact splenocytes is different from NaVO3-induced PLC. Based on these results a model for the sequential activation of substrate-specific PLCs in splenocyte by mitogen is presented.

Animals↗
PubMed1994

Diurnal and acute stress-induced changes in distribution of peripheral blood leukocyte subpopulations.

In this study, we examined hormonal regulation of the distribution profiles of leukocyte subpopulations in the peripheral blood of rats. Flow cytometric analysis revealed significant and selective changes in the numbers and the percentages of peripheral blood leukocyte subpopulations which were a function of diurnal variations in hormone secretion and hormonal changes induced by acute stress. Changes in numbers and percentages of leukocyte subpopulations, which varied with time of day, were similar to changes observed under stress conditions. At the beginning of the rat's active period, and after 1 h of restraint stress, there was a significant reduction in numbers of leukocytes and lymphocytes. This reduction was primarily accounted for by a decrease in numbers of B cells, natural killer cells, monocytes (diurnal study), and helper T cells (diurnal study). There was also a significant decrease in the percentage of lymphocytes which was mirrored by an increase in the percentage of neutrophils in the peripheral blood. Peripheral blood leukocyte numbers were inversely related to plasma corticosterone levels. These results suggest that the endocrine system plays a role in the regulation of immune cell turnover and/or redistribution between immune compartments under conditions of normal daily experiences, namely, the diurnal cycle, and mild acute stress. They also suggest that these effects are selective for certain subpopulations of leukocytes.

Acute Disease↗
PubMed1994

The effects of aging and hormonal manipulation on amyloid precursor protein APP695 mRNA expression in the rat hippocampus.

In the rat hippocampus, neuronal morphology and survival are profoundly affected by adrenal steroids, and synaptic plasticity can be modulated by the ovarian sex steroids estrogen and progesterone. beta-amyloid peptides, which accumulate in neuritic plaques and are derived from the amyloid precursor protein (APP), have been shown to be both trophic and toxic for hippocampal neurons. Of the various APP isoforms, APP695 is the predominant form found in rat brain and the APP695 mRNA is abundantly expressed in the hippocampus. In order to investigate the hypothesis that APP may serve as a mediator of the steroid effects, we have monitored the hippocampal expression of APP695 mRNA by in situ hybridization, with aging and with steroid manipulation. In aged female rats we observed a decrease in the level of APP695 mRNA relative to young female rats, while no such age difference was evident in male rats. Physiological, surgical and pharmacological manipulation of glucocorticoids appeared to have no effect on APP695 mRNA levels in the hippocampus. Treatment of young, ovariectomized female rats with estrogen and progesterone, resulted in an increase in hippocampal APP695 expression compared to untreated, ovariectomized controls.

Adrenalectomy↗
PubMed1994

Effects of selective type I and II adrenal steroid agonists on immune cell distribution.

Adrenal steroids exert their effects through two distinct adrenal steroid receptor subtypes; the high affinity type I, or mineralocorticoid, receptor and the lower affinity type II, or glucocorticoid, receptor. Adrenal steroids have well known effects on immune cell distribution, and although both type I and II receptors are expressed in immune cells and tissues, few data exist on the relative effects mediated through these two receptor subtypes. Accordingly, we administered selective type I and II adrenal steroid receptor agonists to young adult male Sprague-Dawley rats for 7 days and then measured immune cell distribution in the peripheral blood and spleen. Results were compared with those of similar studies using the naturally occurring glucocorticoid of the rat, corticosterone, which binds both type I and II receptors. The majority of the well characterized effects of adrenal steroids on peripheral blood immune cells (increased neutrophils and decreased lymphocytes and monocytes) were reproduced by the type II receptor agonist, RU28362. RU28362 decreased the numbers of all lymphocyte subsets [T-cells, B-cells, and natural killer (NK) cells] to very low absolute levels. The largest relative decrease (i.e. in percentage) was seen in B-cells, whereas NK cells exhibited the least relative decrease and actually showed a 2-fold increase in relative percentage during RU28362 treatment. Similar to RU28362, the type I receptor agonist, aldosterone, significantly reduced the number of lymphocytes and monocytes. In contrast to RU28362, however, aldosterone significantly decreased the number of neutrophils. Moreover, aldosterone decreased the number of T-helper cells and NK cells, while having no effect on the number of B-cells or T-suppressor/cytotoxic cells. Corticosterone at physiologically relevant concentrations had potent effects on immune cell distribution, which were indistinguishable from those of the type II receptor agonist, RU28362. Taken together, these results indicate that effects of adrenal steroids on immune cell distribution are dependent on the receptor subtype involved as well as the specific cell type targeted. These factors allow for varied and complex effects of adrenal steroids on the immune system under physiological conditions.

Aldosterone↗
PubMed1993

Effects of chronic corticosterone ingestion on spatial memory performance and hippocampal serotonergic function.

The effects of chronic ingestion of corticosterone (8 weeks via the drinking water, 400 micrograms/ml) on spatial memory performance and on monoamine levels in brain areas related to memory were investigated. Corticosterone treatment was associated with a long lasting (5 weeks post treatment) increase in 5-HT levels (44%) in the dentate gyrus of the hippocampus and decrease in 5-HT (50%) and NE (36%) levels in the frontal cortex. No effects were found in CA1, CA3 or in nucleus basalis. Performance of the rats on an 8-arm radial arm maze showed no overall effect of corticosterone treatment on trials to criterion or choice accuracy scores. However, three of the treated rats, who had consumed the most corticosterone during treatment, 12.5 +/- 0.3 mg/day, were impaired relative to all subjects. Thus, these results suggest that hippocampal serotonergic terminals show long lasting effects from corticosterone and may also be an early indicator of deleterious effects of glucocorticoids on hippocampal function. However, since only a small number of corticosterone-treated rats showed behavioral changes, future experiments are necessary to address the possibility that a higher level of corticosterone intake alters spatial memory as well as brain morphology and neurochemistry. Additional studies are also needed to determine whether such changes represent a threshold effect of the steroid or a dose-response function.

Administration, Oral↗
PubMed1992

Adrenal steroid receptor activation in rat brain and pituitary following dexamethasone: implications for the dexamethasone suppression test.

The dexamethasone suppression test (DST) has been used extensively to evaluate feedback inhibition of the hypothalamic-pituitary-adrenal (HPA) axis by adrenal steroids. Nevertheless, it remains unclear at what level of the HPA axis and through which adrenal steroid receptor subtype dexamethasone exerts its inhibitory effect. Because adrenal steroid receptor activation is an important prerequisite for dexamethasone to affect cellular function, HPA axis tissues that exhibit evidence of receptor activation following dexamethasone administration are likely site(s) of action for this synthetic hormone to inhibit HPA axis activity. Therefore, type-I and type-II adrenal steroid receptor activation was assessed in the pituitary, hypothalamus, and hippocampus of intact and adrenalectomized rats after overnight exposure to various oral doses of dexamethasone. Results with dexamethasone were compared to similar studies using corticosterone, the endogenous glucocorticoid of the rat. All dexamethasone doses led to significant type-II receptor activation in the pituitary, whereas only an exceedingly high dexamethasone dose activated type-II receptors in the hippocampus and hypothalamus. Dexamethasone had little effect on type I receptors in any tissue at any dose. In contrast, corticosterone significantly activated type-I receptors in all tissues, whereas it activated type-II receptors in the brain and not the pituitary at physiological concentrations. Because dexamethasone activated pituitary type-II receptors at blood concentrations that did not activate type-II receptors in the brain, these results suggest that the DST in humans may primarily be a measure of type-II adrenal steroid receptor feedback inhibition at the level of the pituitary.

Adrenalectomy↗
PubMed1991

Effects of aldosterone or RU28362 treatment on adrenalectomy-induced cell death in the dentate gyrus of the adult rat.

Previous studies have shown that granule cells of the adult dentate gyrus require adrenal steroids for their survival. In order to investigate whether activation of type I or type II adrenal steroid receptors can mediate granule cell survival, we have analyzed the density of pyknotic cells in the granule cell, CA1 and CA3 pyramidal cell layers in Nissl stained hippocampal sections from adult male rats which were either sham operated, adrenalectomized, or adrenalectomized and treated with aldosterone as a specific type I receptor agonist or RU28362 as a specific type II receptor agonist. Aldosterone treatment completely protected the dentate gyrus from adrenalectomy-induced cell death, while treatment with RU28362 resulted in only a partial protection against cell death in this region. These results indicate that type I adrenal steroid receptor activation is sufficient to protect against adrenalectomy-induced cell death.

Adrenalectomy↗
PubMed1991

Corticosterone regulation of type I and type II adrenal steroid receptors in brain, pituitary, and immune tissue.

Type I and Type II adrenal steroid receptor levels were compared in the brain, pituitary and immune system of adrenalectomized rats in the presence or absence of several replacement doses of corticosterone. Six days of adrenalectomy produced an up-regulation of Type II adrenal steroid receptors in the brain and spleen. The lowest replacement dose of corticosterone (equivalent to resting levels of this hormone) blocked this Type II receptor up-regulation, while higher replacement doses of corticosterone were associated with widespread Type I and Type II adrenal steroid receptor down-regulation. However, the dose of corticosterone required for receptor down-regulation varied between tissues. Specifically, hippocampal receptors were most sensitive to corticosterone, whereas pituitary receptors were the least sensitive. All tissues examined, except the pituitary, exhibited a down-regulation of Type II receptors with a high corticosterone replacement dose which approximated acute stress levels of this hormone. In summary, physiologically relevant concentrations of corticosterone were capable of down-regulating Type I and Type II adrenal steroid receptors in multiple brain areas and peripheral immune tissues, including peripheral blood mononuclear cells. In contrast, adrenal steroid receptor levels in the pituitary were relatively insensitive to regulation by corticosterone.

Adrenalectomy↗
PubMed1991

Adrenal steroid receptor activation in vivo and immune function.

Recent studies have indicated significant differences among immune and other tissues in in vivo adrenal steroid receptor activation after a given hormone exposure. Nevertheless, the relationship between in vivo receptor activation and functional measures of the immune response has not been determined. Type I and type II adrenal steroid receptor binding in conjunction with mitogen-induced T-cell proliferative responses were measured in the spleens of Sprague-Dawley rats that were administered various concentrations of dexamethasone (DEX). A linear relationship between type II receptor binding and splenocyte proliferation was found, with decreases in measurable type II receptors (indicating in vivo receptor activation) being highly correlated with decreases in immune function. There was no evidence of spare type II receptors. In vitro studies using the type II receptor antagonist RU 486 confirmed that the inhibitory effect of DEX on splenocyte proliferation was mediated via the type II receptor. These findings provide a foundation for future studies evaluating glucocorticoid effects on immune system function and suggest that evidence of in vivo receptor activation may be critical for predicting when and in which tissues adrenal steroid hormones may be capable of modulating the immune response.

Analysis of Variance↗