Increased natural killer resistance to cyclosporine A by continuous doses of dexamethasone in rats (original) (raw)
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Brain, Behavior, and Immunity, 2014
Most in vitro and ex-vivo studies indicate a profound suppression of NK cell cytotoxicity (NKCC) by glucocorticoids; while catecholamines and prostaglandins were reported both to suppress and to enhance NKCC. However, methodological considerations hinder our ability to deduce from these findings to the impact of endogenous release of these factors on in vivo levels of NKCC and their implications to NK-dependent resistance to pathologies in living humans or animals. Here we used an in vivo approach that sensitively and specifically reflects NKCC in living F344 rats, based on lung clearance of NK-sensitive tumor cells (MADB106), and based on comparing effects between NK-intact and NK-depleted rats. To study the role of corticosterone, epinephrine, and prostaglandins, we administered these factors to rats, or antagonized their endogenous release following different stress paradigms or surgery. The results indicated that endogenous or exogenous elevated corticosterone levels can suppress in vivo NKCC levels, but only under some conditions, and mostly secondarily to the NK-suppressing impact of epinephrine. Specifically, corticosterone-induced NKCC suppression occurred (i) only under prolonged, but not short exposure to stress, and mainly in males; (ii) was smaller than the prominent impact of epinephrine; (iii) was mostly ascribed to corticosterone-induced potentiation of the effects of epinephrine or/and prostaglandins; and (iv) was completely abolished through antagonizing epinephrine or/and prostaglandins. Overall, these findings markedly limit the significance of stress/surgery-induced corticosterone release in the in vivo suppression of NKCC, and highlight the blockade of epinephrine or/and prostaglandins as effective and clinically feasible approaches to overcome such immuno-suppressive effects.
In vivo glucocorticoid effects on porcine natural killer cell activity and circulating leukocytes
Journal of animal science, 1996
Porcine natural killer (NK) cell cytotoxicity, plasma cortisol, total white blood cells (WBC), neutrophil:lymphocyte ratio (N:L), and circulating blood leukocytes were examined from pigs injected i.v. with either saline, ACTH, cortisol, or treated with metyrapone. Plasma cortisol increased (P < .05) after ACTH and cortisol treatments and decreased (P < .05) after metyrapone treatment; thus, treatments had the intended effects on in vivo cortisol concentrations. In Exp. 1, pigs were injected with either saline or ACTH at 0600 after the initial blood samples were taken (time 0). The ACTH had no effect (P > .10) on NK cytotoxicity. Pigs injected i.v. with ACTH had fewer lymphocytes and more neutrophils (P < .05) than control pigs. The N:L ratio was greater (P < .05) among ACTH-injected than among control pigs. In Exp. 2, pigs were injected i.v. with either saline or 40 or 400 micrograms of cortisol at 0600 after the initial blood samples were obtained (time 0). Cortisol ...
European Journal of Immunology, 2004
Corticosteroids are known to inhibit NK cell functions. However no information is available on whether such inhibition may affect the expression and/or the function of receptors involved in NK cell activation. In an attempt to analyze this point, we studied peripheral blood NK cells isolated from pediatric patients undergoing allogeneic BM transplantation. NK cells were analyzed before, during and after methylprednisolone administration to treat acute graftversus-host disease. In NK cells freshly isolated from peripheral blood during methylprednisolone treatment, the surface expression of activating receptors, particularly NKp46 and NKp30, was consistently reduced. Such impaired expression could also be detected after 5 days of culture in IL-2. Such cultured NK cells also failed to express the IL-2-inducible NKp44 receptor. Accordingly, cytotoxicity against different tumor target cell lines was sharply reduced. The effect on NK cells isolated from healthy individuals and cultured in the presence of methylprednisolone was also analyzed. A similar inhibitory effect occurred in the expression of activating NK receptors. In addition, a sharp impairment of NK cytotoxicity against different tumor target cell lines or immature DC was detected.
FEBS Letters, 1991
tZorticosteroids have previously been reported to partially inhibit the natural cytotoxic activity of peripheral blood lymphocytes. I-Iowever, since onIy a few percent of peripheral Iymphocytes are natural killer (NK) cells, it has not been possible to determine whether corticosteroids directly inhibit NK cells or mediate this effect via other cell types. This report documents direct functional inactivation, but unimpeded proliferation, of cloned human NK cells by subphysiologic levels of cortisol. In contrast, high concentrations of testosterone, progesterone or estradiol had no signifi-cI-bt effect on proliferation or cytotoxic activity of the cloned NK cells. The kinetics of inhibition of NK function by cortisol are consistent with a transcription-dependent mechanism. NK cell; Immunoregulation; Cellular cytotoxicity; Cortisol; Corticosteroid Cortisol. testosterone, progesterone and estradiol were purchased from Sigma (St. Louis). Fetal bovine serum with low cortisol content (5.52 nM) was obtained from Hyclone (Logan, Utah) and Lymphocult-T (crude T cell growth factor) from BioTest (Dreieich, Germany). 2. I, Narura! killer ceils The availability of a cloned human NK cell line
Cellular Immunology, 1997
The ability of glucocorticoids to suppress cellular immune functions, including the cytotoxic activity of natural killer cells, is well known. However, the molecular mechanism(s) of glucocorticoid-mediated suppression of cellular cytotoxicity mediated by natural killer cells is not understood. We have investigated the effects of cortisol on protein expression and cytotoxic function of natural killer cells using NK3.3, a wellcharacterized, cloned human natural killer cell line. Cortisol, at concentrations up to 2 pM, does not significantly alter the viability or proliferative capacity of NK3.3 cells. However, micromolar concentrations of cortisol induce the expression of a small set of proteins which are not synthesized by NK3.3 cells in the absence of cortisol, and repress the synthesis of another set of proteins including several phenotypic determinants and cytokines. In the presence of added cortisol, the synthesis of perforin mRNA was partially repressed. However, the most striking effect of cortisol on this NK clone was its repression of granzyme A synthesis. In conjunction with the downregulation of adhesion proteins, NK3.3 cells cultured in the presence of cortisol exhibit a reduced capacity to form conjugates with K562 target cells. Whereas cortisol treatment of NK3.3 cells causes an approximately 50% decrease in their ability to form conjugates with K-562 target cells, the cytotoxic function of these cells is completely abolished under the same conditions. This first report of hormonal regulation of granzyme expression and the strong correlation between granzyme A repression and cytotoxic function suggests that cortisol may regn
Dichotomy of glucocorticoid action in the immune system
Trends in Immunology, 2002
In a vaccination study using inactivated hepatitis A virus (HAV), subjects who had regular sleep following vaccination had a nearly twofold higher anti-HAV antibody titer after four weeks than subjects who stayed awake on the first night after vaccination (T. Lange, Lübeck, Germany). Conditioned immunomodulation Pavlovian conditioning of immune functions provided early impetus to the idea of bidirectional communication between the immune, endocrine and central nervous systems. Using cyclosporin A as an unconditioned stimulus and a novel beverage as the conditioned stimulus, it was demonstrated that re-exposure to the novel beverage alone induced the suppression of lymphocyte proliferation, and IL-2 production and mRNA expression by PBMCs, which was similar to cyclosporin-A-induced immunosuppression (M. Goebel,
Evidence for a beta-adrenoceptor-mediated regulation of human natural killer cells
The Journal of Immunology
Pretreatment of lymphocytes (16 hr, 37 degrees C) with adrenaline at final concentrations of 10(-7) to 10(-9) M, followed by removal of the drug, increased natural killer (NK) cell activity vs K562 leukemic cells in a 4-hr 51Cr-release assay. The most efficient concentration of adrenaline was 10(-8) M; mean increase of NK activity over base-line activity for all donors examined was 30%. However, the individual response to adrenaline pretreatment was variable; in some donors, the effect was equal to maximal interferon (IFN) stimulation. Effects of adrenaline pretreatment were consistently reduced to base-line activity by co-incubation with the nonselective beta-adrenoceptor antagonist propranolol at 100-fold higher concentrations. The enhancing effect of adrenaline (10(-8) M) pretreatment was also observed after 1-hr pretreatment; this effect was prevented by simultaneous incubation with propranolol but was not affected by dex-propranolol. Direct addition of adrenaline to lymphocyte/...
Distinct Effects of Dexamethasone on Human Natural Killer Cell Responses Dependent on Cytokines
Frontiers in immunology, 2017
Glucocorticoids (GCs) have long been known to be immune suppressive and synthetic variants are widely used in the treatment of inflammatory disorders. Here, we report that, while suppressing the initial production of interferon-γ (IFN-γ), the synthetic GC dexamethasone (Dex) enhances the proliferation and survival of natural killer (NK) cells stimulated with interleukin-2 (IL-2) + interleukin-12 (IL-12). Inhibition of mTOR complex 1 by rapamycin revealed the immunosuppressive activity of Dex was independent from the effect of enhancing NK cell proliferation. In the presence of IL-2 + IL-12, Dex also increased the percentage of NK cells that were CD16(+) and DNAM1(bright), increased the level of expression of CD94 or NKG2A, and improved mitochondrial function of NK cells. Moreover, NK cells treated with cytokines IL-2 and IL-12 + Dex, followed by a 7-day rest, displayed an increased IFN-γ response upon restimulation. Thus, there is a dichotomic effect of GCs on NK cell function depen...