The effects of androstenediol and dehydroepiandrosterone on the course and cytokine profile of tuberculosis in BALB/c mice

Abstract

Immunity to Mycobacterium tuberculosis requires a T helper 1 (Th1) cytokine balance accompanied by tumour necrosis factor-alpha (TNF-alpha), and activated macrophages. These facets of the immune response are sensitive to suppression by glucocorticoids (GC), which can reactivate and exacerbate tuberculosis in man and animals. Dehydroepiandrosterone (DHEA) and its derivative, 3beta,17beta androstenediol (AED), are reported to have antiglucocorticoid properties in vivo. We therefore investigated the effects of predetermined optimal doses of these compounds, on the course of pulmonary tuberculosis in an established model in BALB/c mice in which an early phase of Th1-mediated response accompanied by adrenal hyperplasia, is followed by a switch to Th2, progressive loss of TNF-alpha expression and disease progression. Both compounds were protective, particularly AED which caused a fall in bacterial counts and prolonged survival. These effects correlated with the appearance within 3 days of cellular infiltrates rich in cells expressing interleukin-2 (IL-2), IL-1alpha and TNF-alpha, and with partial suppression of the switch to IL-4 producing cells that occurred in controls. AED also caused enhanced development of granulomas at 14 days, and persistence of granuloma formation to 120 days, with a corresponding suppression of areas affected by pneumonia. Much of the therapeutic effect of AED and DHEA was obtained by treating for only the first 3 weeks, which is the phase of adrenal hyperplasia. These results suggest that the ratio of GC to anti-GC steroids may play a role in the pathogenesis of tuberculosis, and further investigation could lead to novel treatment strategies.

Role of the N, N′-dimethylbiguanide metformin in the treatment of female prepuberal BALB/c mice hyperandrogenized with dehydroepiandrosterone

“…Subsequent studies established that the DHEA-PCOS murine model exhibits some of the salient features of human PCOS, such as hyperandrogenism, abnormal maturation of ovarian follicules and anovulation (Lee et al 1991, Anderson et al 1992, Henmi et al 2001. These findings, together with the fact that increasing evidence indicates that DHEA has, in addition, potent immunoregulatory functions (Meikle et al 1992, Okabe et al 1995, Hernandez Pardo et al 1998, Zhang et al 1999) led us to use the DHEA-mice model to study some aspects related to the endocrine and immune responses involved.…”

Conversion of dehydroepiandrosterone to downstream steroid hormones in macrophages

“…DHEA supplementation had beneficial effects in human SLE (van Vollenhoven et al 1998) and murine models of SLE (Lucas et al 1985), in atherosclerosis models in rabbits (Gordon et al 1988), virus or parasite infection in rodents (Rasmussen et al 1995, Loria et al 1988, mouse tuberculosis (Hernandez-Pando et al 1998), and in an animal model of type 2 diabetes with elevated serum tumor necrosis factor (TNF) (Kimura et al 1998). The common reason for the positive effects of DHEA in the mentioned chronic diseases is probably inhibition of NF-B (Yamada et al 1994, Spencer et al 1997.…”

Administration of Dehydroepiandrosterone Suppresses Experimental Allergic Encephalomyelitis in SJL/J Mice

“…In animal model systems, administration of DHEA enhances the ability of mice to resist experimental viral and bacterial diseases (15)(16)(17)(18)(19)(20). In humans, many chronic inflammatory diseases are associated with lower serum levels of DHEA or DHEAS (21).…”