No abstract

We have investigated the relationship between cortisol and dehydroepiandrosterone (DHEA) levels and the immune response to mycobacterial antigens in peripheral venous blood, from a male population of active tuberculosis patients and age‐matched healthy controls of the same sex (HCo). Peripheral blood mononuclear cells were cultured for 36 or 96 h with whole sonicated Mycobacterium tuberculosis (WSA) for measurement of proliferation, interferon gamma (IFN‐γ) and interleukin‐10 (IL‐10) in culture supernatants. Comparisons on the in vitro mycobacterial‐driven immune responses demonstrated that TB patients had a higher IL‐10 production, a decreased lymphoproliferation and a trend to reduced IFN‐γ synthesis, in relation to HCo. Active disease was also characterized by increases in the plasma levels of glucocorticoids (GC) and reduced concentrations of DHEA which resulted in a higher cortisol/DHEA ratio respect the HCo group. Plasma DHEA levels were positively correlated with IFN‐γ values. An inverse correlation was found between the cortisol/DHEA ratio and IFN‐γ levels. Novel evidence is provided showing that the balance between cortisol and DHEA is partly responsible for the immune perturbations seen in TB patients.

Administration of IL-1␤ results in a profound and long-lasting hypoglycemia. Here, we show that this effect can be elicited by endogenous IL-1 and is related to not only the capacity of the cytokine to increase glucose uptake in peripheral tissues but also to mechanisms integrated in the brain. We show that (i) blockade of IL-1 receptors in the brain partially counteracted IL-1-induced hypoglycemia; (ii) peripheral administration or induction of IL-1 production resulted in IL-1␤ gene expression in the hypothalamus of normal and insulin-resistant, leptin receptor-deficient, diabetic db͞db mice; (iii) IL-1-treated normal and db͞db mice challenged with glucose did not return to their initial glucose levels but remained hypoglycemic for several hours. This effect was largely antagonized by blockade of IL-1 receptors in the brain; and (iv) when animals with an advanced Type II diabetes were treated with IL-1 and challenged with glucose, they died in hypoglycemia. However, when IL-1 receptors in the brains of these diabetic mice were blocked, they survived, and glucose blood levels approached those that these mice had before IL-1 administration. The prolonged hypoglycemic effect of IL-1 is insulin-independent and develops against increased levels of glucocorticoids, catecholamines, and glucagon. These findings, together with the present demonstration that this effect is integrated in the brain and is paralleled by IL-1␤ expression in the hypothalamus, indicate that this cytokine can reset glucose homeostasis at central levels. Such reset, along with the peripheral actions of the cytokine, would favor glucose uptake by immune cells during inflammatory͞ immune processes.T here is evidence that immune-derived cytokines can mediate metabolic alterations during the course of infective, inflammatory, autoimmune, and neoplastic processes (1-4), either by acting locally or by interacting with different endocrine mechanisms (2, 3, 5). Under physiological conditions, glucose is the principal and most readily available source of energy. When IL-1, a prototypic proinflammatory cytokine, is administered to mice, a profound and long-lasting hypoglycemia is observed. The hypoglycemic effect of IL-1 is not mediated by insulin, because it is clearly observed in insulin-resistant diabetic mice and rats; is not caused by glucose loss; and is independent from the anorexic effect of the cytokine (6-12). IL-1-induced hypoglycemia might be explained by the capacity of this cytokine to stimulate glucose uptake in vitro in a variety of tissues such as adipose cells (13), fibroblasts (14), articular chondrocytes (15), keratinocytes (16), intestinal macrophages (17), peritoneal mesothelial cells (18), and glial cells (19). Studies in vivo also show that overproduction of IL-1 results in increased 2-deoxyglucose uptake in all tissues tested, including lymphoid organs and the brain (20). Several of the mentioned in vitro studies on the effect of IL-1 on glucose transport have been performed by using human cells, and injection of very low doses of...

The effect of cortisol and/or dehydroepiandrosterone (DHEA) on the immune response to antigens obtained from Mycobacterium tuberculosis was studied in vitro by using peripheral blood mononuclear cells obtained from patients at various stages of lung tuberculosis (TB) and from healthy control people (HCo). The results obtained show for the first time that addition of cortisol within concentrations of physiological range can inhibit the mycobacterial antigendriven proliferation of cells from HCo and TB patients and the production of interferon-g (IFN-g), indicating that endogenous levels of cortisol may contribute to the decreased lymphoid cell response to mycobacterium antigens observed in TB patients. DHEA did not affect lymphoid cell proliferation, IFN-g production and the cortisol-mediated inhibitory effects. Interestingly, we found that DHEA, but not cortisol, suppressed the in vitro transforming growth factor-b production by lymphoid cells from TB patients with an advanced disease, which is indicative of a selective direct effect of this hormone.

The study’s objective was to examine whether factors related to the host status may bear some relation with the profile of the immune response displayed by tuberculosis (TB) patients. The in vitro immune response (antigen-driven lymphoproliferation and cytokine production) and the presence of alcoholism or disease-related factors, like heart and respiratory rates, and weight loss (body mass index, BMI) were investigated in 31 males with active, untreated TB. Compared to 16 age-matched healthy males, TB patients presented depressed lymphoproliferation and increased IL-10 and TGF-β production. Multivariate analysis indicated that most differences were no longer significant when controlling for the BMI. Immune and endocrine changes coexisting with weight loss, such as circulating levels of TNF-α, IFN-γ, IL-6, cortisol, dehydroepiandrosterone and thyroid hormones, were also analyzed. While pairwise correlations between serum levels of IFN-γ, T3 or T4 and BMI were not significant, BMI was negatively correlated with IL-6 levels (p < 0.025). In turn, levels of IL-6 correlated positively with cortisol concentrations (p <0.001). Stepwise regression analysis demonstrated that BMI was only associated with IL-6 (r = –0.423, R² = 0.18), with the difference remaining significant following adjustment for the other variables. As regards IL-6, BMI, cortisol and IFN-γ could explain 74% of variability in IL-6 concentrations (R² = 0.74). No evidence for effect modification was shown when performing adjusted calculations. To conclude, the relation between weight loss and abnormal immune response of TB patients is partly associated with the immunoendocrine imbalance observed in parallel.