Dehydroepiandrosterone protects mice from endotoxin toxicity and reduces tumor necrosis factor production

Abstract

Recent reports have demonstrated an immunomodulating activity of dehydroepiandrosterone (DHEA) different from that described for glucocorticoids. The present study was designed to test DHEA's activity in endotoxic shock and to investigate its effect on endotoxin-induced production of tumor necrosis factor (TNF).Mortality of CD-1 mice exposed to a lethal dose of lipopolysaccharide (LPS; 800 ,ug per mouse) was reduced from 95 to 24% by treatment with a single dose of DHEA, given 5 min before LPS. LPS administration resulted in high levels of TNF, a response that was significantly blocked by DHEA, both in vivo and in vitro. DHEA treatment also reduced LPS-induced increments in serum corticosterone levels, a parameter considered not to be mediated by TNF. In another experimental model, mice sensitized with D-galactosamine, followed by administration of recombinant human TNF, were subjected to 89% mortality rate, which was reduced to 55% in DHEA-treated mice. These data show that DHEA protects mice from endotoxin lethality. The protective effect is probably mediated by reduction of TNF production as well as by effecting both TNF-induced and non-TNF-induced phenomena.Dehydroepiandrosterone (DHEA) is an abundantly secreted, weak androgenic, adrenocortical steroid hormone that is an intermediate in the biosynthesis of other hormones including testosterone and estradiol-171. Concentrations of DHEA in plasma gradually decline after the third decade of life, reaching 10 to 20% of the peak level in the e!derly (20,24).The precise biological functions of DHEA are uncertain. A growing body of evidence, both experimental and epidemiological, suggests an inverse relationship between low levels of DHEA in serum and morbidity from atherosclerotic cardiovascular disease (1, 9), cancer (10,11,26) and human immunodeficiency virus (HIV) infection (31). Moreover, low levels of DHEA were found to be independently predictive of death from any cause (1).Recent reports proposed an immunomodulating activity of DHEA. It was found to prevent dexamethasone-induced thymic involution in mice (19), increase interleukin-2 production both in vitro and in vivo (6), and prevent the development of systemic lupus erythematosus in a mouse model (18). Lymphopoiesis, but not myelopoiesis or erythropoiesis, was inhibited in irradiated mice fed with DHEA (28, 29). Although lacking an in vitro antiviral activity, DHEA was effective in protecting mice from a variety of lethal viral infections (2, 17).During the course of gram-negative infections, bacterial cell wall products, such as endotoxin (lipopolysaccharide [LPS]), are released, inducing intense pathophysiologic alterations (22). It is not LPS alone that causes the damage, but rather the host response, which may be described as an "overshoot" of the immune system. One of the major responses to LPS in vivo is the rapid production and secretion of cytokines, the soluble mediators of inflammation, like tumor necrosis factor (TNF) (3,5).LPS toxicity can be reduced by administration of potent immunosuppresi...

Are alterations of lymphocyte subpopulations in polymicrobial sepsis and DHEA treatment mediated by the tumour necrosis factor (TNF)-αreceptor (TNF-RI)? A study in TNF-RI (TNF-RI–/–) knock-out rodents

“…Considering the results of previous studies, it has been proposed that DHEA acts by decreasing plasma TNF-a levels [15,19]. However, in the current study a significant improvement in survival rates was also demonstrated in TNF-RI -/-mice following DHEA administration, demonstrating clearly that its main effect on mortality is not via the TNF-RI.…”

“…DHEA has also been shown to modulate prednisone-induced immune suppression, resulting in higher survival rates following Gram-negative sepsis. This improvement in cellular immune function is associated with reversal of sepsis-related delayed-type hypersensitivity depression [15]. The administration of DHEA to healthy volunteers has been associated with reduced plasma levels of CD4 + and increased CD8…”

Reduction in the incidence and severity of collagen‐induced arthritis in DBA/1 mice, using exogenous dehydroepiandrosterone

“…There was no obvious difference in the arthritis severity in these mice compared with the vehicle-only controls (data not shown). It was therefore decided that the DHEA dose and its frequency would be increased, since it had been reported that mice could be protected from potentially lethal endotoxin challenge at doses of -1 mg/mouse (10 show that repeated DHEA injections at 1 mg/mouse delayed the onset and reduced the severity at the CIA. Three of the 6 mice in the vehicle-only control group died early in the experiment (between days 6 and 15), compared with none in the DHEA-plus-vehicle group.…”

Stress responses and innate immunity: aging as a contributory factor

“…DHEA influences a variety of immune parameters (Table 1) and administration of DHEA increases host resistance to viral and bacterial pathogens in animal studies , 1999Danenberg et al ., 1992;Loria et al ., 1996). Furthermore, animal studies also suggest that DHEA could overcome the immune suppressive effects of trauma.…”