Suppressive Effect Of Glucocorticoids Research Articles

Increased serum soluble CD8 or suppressor/cytotoxic antigen concentrations in depression: Suppressive effects of glucocorticoids

There is now some evidence that depression and, in particular, major depression, is accompanied by signs of an immune response, and that there are reciprocal relationships between immune function and increased hypothalamic-pituitary-adrenal (HPA) axis activity in depression. To further examine the above phenomena, this study has assayed serum soluble CD8 (sCD8) concentrations in 22 normal controls, 27 minor depressed, 37 major depressed, and 26 melancholic depressed patients. Serum sCD8 was significantly higher in depressed patients versus normal controls. Thirty-five percent of the depressed subjects had increased sCD8 serum levels (i.e., > 560 U/mL) with a specificity of 95.4%. Dexamethasone administration (1 mg PO) had a significant suppressive effect on serum sCD8. In depressed subjects, there were significant and negative relationships between serum sCD8 and postdexamethasone cortisol values. The results suggest the presence of an ongoing lymphocyte activation in depression, which may be down-regulated by increased HPA axis activity in that illness.

Suppression of lymphocyte interleukin-2 receptor expression by glucocorticoids, cyclosporine, or both.

Although glucocorticoids and cyclosporine are frequently used to treat patients with various types of glomerulopathy, clinical responses to treatment vary considerably. Considerable interindividual heterogeneity in the suppressive effects of glucocorticoids on lymphocyte proliferation in vitro has been previously reported, suggesting that differences in the pharmacodynamic responsiveness of the immune system to these agents might be an important determinant of how well an individual patient responds to treatment. It also has been shown that methylprednisolone is significantly more suppressive than prednisolone. To identify cellular mechanisms by which these drugs act, a study of the suppressive effects of prednisolone, methylprednisolone, and cyclosporine on lymphocyte proliferation and the expression of the cell surface receptor for interleukin-2 (IL-2R) was conducted using phytohemagglutin-stimulated peripheral blood mononuclear cells (PBMCs) from 13 patients with glomerulopathy and 12 control subjects. Heterogeneity among individuals in both parameters of lymphocyte responsiveness to these drugs was again found, and the significantly greater suppressive effect of methylprednisolone was confirmed for both proliferation and IL-2R expression in patients and control subjects. Cyclosporine alone was moderately suppressive. For most individuals, the greatest degree of suppression occurred when cells were exposed to both cyclosporine and glucocorticoid. Further studies are being conducted to determine whether pretreatment assessment of in vitro lymphocyte responsiveness has any predictive value regarding therapeutic efficacy of each drug in individual patients and to identify of those patients likely to require a more intensive or multidrug immunosuppressive regimen.

Glucocorticoid inhibition of antigen-induced inositol phosphate formation: possible involvement of phosphatases.

The suppressive effect of glucocorticoids (GC) upon antigen-induced phosphatidylinositol phospholipase C (PI-PLC) activity and inositol phosphate formation by rat basophilic leukemia cells (RBL-2H3) has been characterized. Addition of antigen for a period of 1-30 min enhanced production of [3H]inositol monophosphate (IP1), inositol 1,4-biphosphate (IP2) and inositol 1,4,5-triphosphate (IP3) by about 5-10 fold. Pretreatment with hydrocortisone (HC) and dexamethasone (DEX) reduced formation of the various inositol phosphates (IPs) and degradation of phosphatidylinositol-4-5-biphosphate (PIP2) by an average of 50% Antigen-stimulated phosphorylation of an 18 kDA and other proteins was inhibited by about 60% following pretreatment with the GC. This inhibition was in turn prevented by cycloheximide. Moreover, DEX doubled cellular acid phosphatase activity. The results suggest that the inhibitory effect of GC is possibly mediated, among other things, by protein phosphatase activity.

Isolated pituitary cells: glucocorticoids do not rapidly suppress ACTH secretion in response to CRF

The possibility of a direct rapid suppressive effect of glucocorticoids on stimulated adrenocorticotropic hormone (ACTH) release was investigated in perifused normal pituitary cells attached to microcarriers. Forty-eight hours after attachment to Cytodex beads, cells were transferred to two columns (one experimental, one control), perifused at a rate of 300-350 microliters/min, and equilibrated for 3 h. Either rat or ovine corticotropin-releasing factor (CRF; 2 nM) were used to stimulate ACTH release, and fractions collected every 5 min were assayed for immunoreactive ACTH. Concomitant treatment with CRF and glucocorticoids (dexamethasone 100 nM or corticosterone 1 microM), or glucocorticoid pretreatment for up to 2 h, did not affect the release of ACTH occasioned by repetitive 5-min exposures to CRF at 30-min intervals. In addition, when ovine CRF was given as two 30-min infusions 1 h apart, neither concomitant steroid administration nor steroid pretreatment for 90 min affected the release of ACTH compared with controls. The lack of rapid steroid inhibition was not an artifact of enzymatic dispersion or microcarrier attachment, since no rapid inhibitory response was seen with acutely perifused rat anterior pituitary quarters. We thus conclude that in vitro rapid inhibitory effects of glucocorticoids on ACTH release do not occur at the level of the pituitary. Accordingly such action in vivo presumably reflects acute steroid-induced effects on the hypothalamus or higher centers.

Corticosteroid receptors in the kidney of chick embryo II. Ontogeny of corticosterone receptor and cellular development

In this study the ontogeny of cytosol receptors for corticosterone in the chick embryo kidney was examined and then this ontogenic profile was compared with that of an index of cellular development, i.e., the enzyme ornithine decarboxylase (ODC). The corticosterone receptor concentration ( n max) increased by sevenfold from Day 12 to Day 15 of embryogenesis and then declined to its lowest level by the time of hatching (Day 21). Similar results were obtained when dexamethasone was used as ligand, except that the baseline values at Day 9 and 21 were higher than those found with corticosterone. An identical ontogenic profile was obtained when the results were corrected for the endogenous glucocorticoids present in the cytosol. This increase of the corticosterone receptor occurred simultaneously with the enhanced adrenal corticoid synthesis. The ODC also showed a marked increase and a rapid fall during chick embryogenesis, but the enzyme activity was at its maximum when the corticosterone receptor number was still low (Days 12 and 13) and quickly decreased by the time the receptors had reached their highest levels (Days 14 and 15). The lowest level of ODC was observed immediately before hatching. These results indicate that during chick embryogenesis adrenal corticoids may induce the development of the corticosteroid receptor and that such development may cause a suppression of ODC activity. This suppressive effect of glucocorticoids could represent a mechanism of hormonal action on the kidney.

Lymphocytes bearing Fc receptors for IgE. VI. Suppressive effect of glucocorticoids on the expression of Fc epsilon receptors and glycosylation of IgE-binding factors.

Incubation of rat lymphocytes with homologous IgE induced an increase in Fc epsilon R(+) lymphocytes and the formation of IgE-binding factors. Pretreatment of rat lymphocytes with 1 to 5 microM dexamethasone, however, prevented the IgE-induced expression of Fc epsilon R on both B and T lymphocytes. Upon incubation with IgE, T cells activated with 10 micrograms/ml Con A produced IgE-potentiating factors that had affinity for lentil lectin and selectively enhanced the IgE response. Pretreatment of the Con A-activated T cells with dexamethasone, before incubation with IgE, changed the nature of IgE-binding factors formed by the cells. The majority of IgE-binding factors formed by the dexamethasone-treated, Con A-activated cells failed to bind lentil lectin Sepharose and selectively suppressed the IgE response. An injection of 0.2 mg dexamethasone into rats infected with Nippostrongylus brasiliensis markedly diminished the proportion of Fc epsilon R(+) lymphocytes in their mesenteric lymph nodes. The lymph node cells from the infected animals spontaneously released IgE-potentiating factors in vitro. However, the majority of IgE-binding factors formed by the mesenteric lymph node cells from the dexamethasone-treated, Nb-infected animals lacked affinity for lentil lectin and selectively suppressed the IgE response. The results indicate that glucocorticoid treatment prevented the glycosylation of IgE-binding factors and thereby changed the biologic activities of the factors.