Suppressive Effects Of Cortisol Research Articles

Effects of cortisol and lipopolysaccharide on expression of select growth-, stress- and immune-related genes in rainbow trout liver

Many studies have shown that stress-induced cortisol levels negatively influence growth and immunity in finfish. Despite this knowledge, few studies have assessed the direct effects of cortisol on liver immune function. Using real-time PCR, the expression of three cortisol-responsive genes (GR: glucocorticoid receptor, IGF-1: insulin-like growth factor-I and SOCS-1: suppressor of cytokine signaling-I), genes involved with innate and adaptive immunity (IL-1β: interleukin-1 beta, IgM: immunoglobin-M and Lyz: lysozyme), and liver-specific antimicrobial peptides (hepcidin and LEAP-2A: liver-expressed antimicrobial peptide-2A) was studied in vitro using rainbow trout liver slices. The abundances of GR, SOCS-1 and IGF-1 mRNAs were suppressed by cortisol treatment. Abundance of IL-1β mRNA was upregulated by LPS and suppressed by cortisol treatment in a time-dependent manner. While abundance of IgM mRNA was suppressed by cortisol treatment and stimulated by LPS, there were no effects of cortisol or LPS on abundance of Lyz mRNA. Abundance of hepcidin and LEAP-2A mRNA levels were suppressed by cortisol treatment and stimulated by LPS. These results demonstrate that cortisol directly suppresses abundance of GR, IGF-1, IL-1β, IgM, hepcidin, LEAP-2A and SOCS-1 mRNA transcripts in the rainbow trout liver. We report for the first time, a suppressive effect of cortisol (within 8 h of treatment) on hepcidin and LEAP-2A mRNAs in rainbow trout liver, which suggests that acute stress may negatively affect liver immune function in rainbow trout.

Circadian characteristics of permissive and suppressive effects of cortisol and their role in homeostasis and the acute inflammatory response

In this work we explore a semi-mechanistic model that considers cortisol's permissive and suppressive effects through the regulation of cytokine receptors and cytokines respectively. Our model reveals the proactive role of cortisol during the resting period and its reactive character during the body's activity phase. Administration of an acute LPS dose during the night, when cortisol's permissive effects are higher than suppressive, leads to increased cytokine levels compared to LPS administration at morning when cortisol's suppressive effects are higher. Interestingly, our model presents a hysteretic behavior where the relative predominance of permissive or suppressive effects results not only from cortisol levels but also from the previous states of the model. Therefore, for the same cortisol levels, administration of an inflammatory stimulus at cortisol's ascending phase, that follows a time period where cytokine receptor expression is elevated ultimately sensitizing the body for the impending stimulus, leads to higher cytokine expression compared to administration of the same stimulus at cortisol's descending phase.

Cyclic changes in cortisol across the estrous cycle in parous and nulliparous Asian elephants

In the context of reproduction, glucocorticoids (GCs) are generally considered to have negative effects. However, in well-studied model species, GCs fluctuate predictability across the estrous cycles, and short-term increases promote healthy ovarian function. Reproductive challenges have plagued captive elephant populations, which are not currently self-sustaining. Efforts to understand reproductive dysfunction in elephants have focused on the suppressive effects of cortisol, but the potential permissive or stimulatory effects of cortisol are unknown. In this study, we provide a detailed examination of cortisol patterns across the estrous cycle in Asian elephants (Elephas maximus). Time series analysis was used to analyze cortisol and progesterone data for a total of 73 cycles from eight females. We also compared cortisol profiles between females that successfully conceived and females that failed to conceive despite repeated mating attempts. Our results revealed that cortisol fluctuates predictably across the estrous cycle, with a peak during the second half of the follicular phase followed by low levels throughout the luteal phase. Furthermore, this pattern was significantly altered in nulliparous females; cortisol concentrations did not decline during the luteal phase to the same extent as in parous females. This study highlights the complexity of cortisol signaling and suggests future directions for understanding the role of cortisol in reproductive dysfunction.

Sex Difference in the Suppressive Effect of Cortisol on Pulsatile Secretion of Luteinizing Hormone in Sheep

We tested the hypothesis that there are sex differences in the inhibitory effect of cortisol on pulsatile LH secretion and pituitary responsiveness to GnRH in gonadectomized sheep. In experiment 1, pulsatile LH secretion was examined in gonadectomized ewes and rams infused with either saline, a low (250 microg/kg.h) or a high (500 microg/kg.h) dose of cortisol for 30 h. In experiment 2, direct pituitary actions of cortisol were assessed by monitoring LH pulse amplitude in response to exogenous GnRH in hypothalamo-pituitary disconnected ewes and rams infused with the low dose of cortisol. In experiment 1, the mean (+/-sem) plasma LH concentration was (P<0.05) reduced significantly during cortisol infusion in both sexes, but the effect was greater in rams. In ewes, LH pulse amplitude and frequency were reduced (P<0.05) at the high, but not the low, cortisol dose, whereas total LH output (LH pulse amplitude multiplied by frequency) was reduced (P<0.05) at both doses. In rams, LH pulse frequency and amplitude and total LH output were (P<0.05) reduced significantly at both cortisol doses. In experiment 2, plasma LH concentration and pulse amplitude in response to exogenous GnRH were not affected by infusion of cortisol in either sex. We conclude that gonadectomized rams are more sensitive than gonadectomized ewes to the effects of cortisol to inhibit LH secretion and that sex differences exist in the specific actions of cortisol on LH pulses. The results of experiment 2 suggest that intact hypothalamic input to the pituitary is necessary for cortisol to inhibit pituitary responsiveness to GnRH.

Modeling interactions between adrenal suppression and T-helper lymphocyte trafficking during multiple dosing of methylprednisolone.

A physiologic pharmacodynamic model was developed to jointly characterize the effects of corticosteroid treatment on adrenal suppression and T-helper cell trafficking during single and multiple dosing in asthmatic patients. Methylprednisolone (MP), cortisol, and T-helper cell concentrations obtained from a previously published study during single day and 6 days of multiple dosing MP treatment were examined. The formation and disposition kinetics of MP were described with a compartmental model. The biorhythmic profile of basal cortisol secretion rate was analyzed using a recent Fourier approach based on circadian harmonics. A three-compartment loop model was proposed to represent three major T-helper cell pools: blood, extravascular site, and lymph nodes. T-helper cell synthesis and degradation rate constants were obtained from the literature. The suppressive effects of cortisol and MP on T-helper cell concentrations were described with a joint additive inhibition function altering the cell migration rate from lymph nodes to blood. The model adequately described both plasma cortisol profiles and T-helper cells in blood after single and multiple doses of MP. The potency of MP for suppression of cortisol secretion was estimated as IC50 = 0.8 ng/ml. The biorhythmic nature of the basal T-helper cells in blood was well described as under the influence of basal circadian cortisol concentrations with IC50 = 79 ng/ml. The model fitted potency of MP for suppression of T-helper cells was IC50 = 4.6 ng/ml. The observed rebound of T-helper cells in blood can also be described by the proposed model. The rhythm and suppression of plasma cortisol and T-helper cells before and during single and multiple dose MP treatment were adequately described by these extended indirect response models.

Cortisol Inhibits the Synthesis of Insulin-like Growth Factor-binding Protein-5 in Bone Cell Cultures by Transcriptional Mechanisms

Glucocorticoids inhibit the synthesis of insulin-like growth factor-binding protein-5 (IGFBP-5) in osteoblasts, but the mechanisms involved are unknown. IGFBP-5 stimulates bone cell growth, and its inhibition by glucocorticoids may be relevant to the action of this binding protein on bone formation. We tested the effects of cortisol on IGFBP-5 expression in cultures of osteoblast-enriched cells from fetal rat calvariae (Ob cells). Cortisol decreased IGFBP-5 polypeptide levels in the extracellular matrix and caused a time- and dose-dependent decrease in IGFBP-5 mRNA. IGFBP-5 transcripts were markedly decreased by cycloheximide, and further suppressive effects of cortisol could not be determined. Cortisol did not modify the decay of IGFBP-5 mRNA in transcriptionally arrested Ob cells. Cortisol decreased IGFBP-5 hnRNA, the rate of IGFBP-5 transcription, and the activity of the murine IGFBP-5 promoter by 35% in transient transfection experiments. Deletion analysis showed that the region responsive to cortisol is from base pairs -70 to +22, and E-box-binding proteins or c-Myb-related nuclear factors may be involved in its regulation. In conclusion, cortisol inhibits IGFBP-5 transcription in Ob cells through the Myb-binding domain. This effect may be partly responsible for the effect of glucocorticoids on bone formation.

Effects of cortisol and stress on the immune system in Atlantic Salmon ( Salmo salarL.)

A suppressive effect of cortisol on LPS mitogenesis was demonstrated on peripheral blood cells from Atlantic salmon ( Salmo salarL.) in vitro, and the suppression was dose and time dependent. When cortisol was injected intraperitoneally into fish, there was a rapid increase in the level of cortisol in the blood which was, however, effectively cleared from the circulation within a few hours. The number of cells in the various populations of blood leucocytes was counted after cortisol administration demonstrating a marked increase in the relative number of thrombocytes, while the number of granulocytes, monocytes and lymphocytes was relatively constant. Qualitatively, however, the lymphocytes seemed to be affected by cortisol, since the number of Ig positive cells were dramatically downregulated during the first days after cortisol injection. A significant reduction in the mitogenic response of blood lymphocytes to LPS was also observed and the response gradually returned to normal levels over the next four days. When Atlantic salmon were exposed to repeated handling stress, there was no significant difference in the total immunological status compared to non-stressed fish as judged by antibody production and protection against Aeromonas salmonicidainfection.

Seasonal changes in cortisol sensitivity and glucocorticoid receptor affinity and number in leukocytes of coho salmon

To determine if there were organ-specific changes in immune responses or immune-endocrine interaction, we monitored in vitro immune response, cortisol sensitivity and number and affinity of glucocorticoid receptors (GR) in leukocytes from freshwater-adapted juvenile coho salmon (Oncorhynchus kisutch) during the physiological changes that prepare them to enter the marine environment. During this period, absolute immune response declined, but splenic leukocytes generated more antibody-producing cells than did cells from anterior kidney. Splenic leukocytes were initially more sensitive to the suppressive effects of cortisol and had fewer GR than leukocytes from the anterior kidney. Leukocytes from the anterior kidney were initially insensitive to cortisol but developed sensitivity at about the same time as the dissociation constant and number of GR increased. In vitro incubation of anterior kidney leukocytes in cortisol altered GR variables when experiments were conducted during March through September but not during November through February. In some years, changes in GR or immune responses were correlated with plasma cortisol titers, but in other years there was no correlation. Thus, the exact relation between cortisol, GR and immune response in anadromous salmonids is unclear and other factors are involved.

Interaction between cortisol and arachidonic acid on the secretion of LH from ovine pituitary tissue

In several species, glucocorticoids act directly on the pituitary gonadotroph to suppress the gonadotrophin-releasing hormone (GnRH)-induced secretion of the gonadotrophins, especially LH. A mechanism for this action of these adrenal steroids has not been established, but it appears that the glucocorticoids influence LH release by acting on one or more post-receptor sites. This study investigated whether glucocorticoids disrupt GnRH-induced LH release by altering the liberation of arachidonic acid from plasma membrane phospholipids, a component of GnRH-induced LH release. Using perifused ovine pituitary tissue, it was established that exposure of gonadotrophs to 1-1000 nmol cortisol/l for 4 h or longer significantly reduced GnRH-stimulated LH release with the maximal inhibitory effect being observed after 6 h of exposure to cortisol. This suppressive effect of cortisol could be reversed by administration of arachidonic acid, which in its own right could stimulate LH release from ovine pituitary tissue. Furthermore, the inhibitory effect of cortisol on GnRH-stimulated LH release could be directly correlated with decreased pituitary responsiveness to GnRH-stimulated arachidonic acid liberation, consistent with our hypothesis that glucocorticoids can suppress GnRH-induced secretion of LH by reducing the amount of arachidonic acid available for the exocytotic response of GnRH.

The effects of RU 486 on immune function and steroid-induced immunosuppression in vitro.

The effect of RU 486 [17 beta-hydroxy-11 beta-(4-dimethylamino-phenol)17 alpha-(prop-1-ynyl)estra- 4,9diene-3-one] on [3H]thymidine incorporation into Concanavalin-A-stimulated human peripheral blood mononuclear cells and its influence on the suppressive effects of cortisol and progesterone were investigated. Cortisol suppressed lymphocyte thymidine incorporation at 10(-5), 10(-6), and 10(-7) M (17.6%, 20%, and 38% of control, respectively; P less than 0.01). Cortisol-induced suppression was reversed when low concentrations of RU 486 (10(-7) and 10(-6) M) were added. RU 486 at 10(-5) M further suppressed lymphocyte thymidine incorporation when added to cultures with cortisol. Progesterone significantly inhibited lymphocyte thymidine incorporation at 10(-5) M (8.2% of control; P less than 0.01). No reversal of progesterone-induced suppression of thymidine incorporation was seen when RU 486 was added to cultures; rather, further suppression of thymidine incorporation was seen. RU 486 alone in culture at concentrations achieved therapeutically (10(-5) M) significantly inhibited thymidine incorporation (7.2% of control; P less than 0.01). These findings suggest that RU 486 may have dose-dependent mixed agonist/antagonist effects on cortisol-induced immunosuppression. The lack of an antagonist effect of RU 486 on progesterone suggests that progesterone's immunosuppressive effects may not be receptor mediated. Finally, our findings would suggest that some immunosuppression may be seen at currently used doses of RU 486.

Changes in adrenal gland and thymus induced by sex steroid administration in newborn rats (author's transl)

Testosterone, dehydroepiandrosterone (DHEA), progesterone, estradiol-17beta, estrone, estriol, 2-hydroxyestradiol-17beta, 2-hydroxyestriol, deoxyestrone and diethylstilbestrol were injected s.c. in a dose of 0.5 mg each into newborn rats on the first day of life, and changes in the adrenal gland, thymus and spleen were examined 3 days later. Increase in the body weight during the 3 days was less in rats treated with DHEA, 2-hydroxyestriol and deoxyestrone, as compared with that in controls. Development of the thymus was significantly impaired in rats injected with various kinds of sex steroids, except progesterone and diethylstilbestrol. Reduction of the spleen weight by sex steroid treatment was not marked. The weight of adrenal gland decreased in rats injected with DHEA and progesterone, while the weight increased in those given estrone and diethylstilbestrol. Estrogens, particularly estriol, induced a marked increase in adrenal corticosterone content, while 2-hydroxyestriol caused only slight elevation and 2-hydroxyestradiol and deoxyestrone had no influence on the content. Suppressive effect of cortisol on the adrenal gland of newborn rats was slightly, but significantly, lessened by estriol treatment. From the results, physiological role of estriol and DHEA in adrenal secretion was discussed.