Dehydroepiandrosterone and metyrapone partially restore the adaptive humoral and cellular immune response in endotoxin immunosuppressed mice

Abstract

Prior exposure to endotoxins renders the host temporarily refractory to subsequent endotoxin challenge (endotoxin tolerance). Clinically, this state has also been pointed out as the initial cause of the non-specific humoral and cellular immunosuppression described in these patients. We recently demonstrated the restoration of immune response with mifepristone (RU486), a receptor antagonist of glucocorticoids. Here we report the treatment with other modulators of glucocorticoids, i.e. dehydroepiandrosterone (DHEA), a hormone with anti-glucocorticoid properties, or metyrapone (MET) an inhibitor of corticosterone synthesis. These drugs were able to partially, but significantly, restore the humoral immune response in immunosuppressed mice. A significant recovery of proliferative responsiveness was also observed when splenocytes were obtained from DHEA- or MET-treated immunosuppressed mice. In addition, these treatments restored the hypersensitivity response in immunosuppressed mice. Finally, although neither DHEA nor MET improved the reduced CD4 lymphocyte count in spleen from immunosuppressed mice, both treatments promoted spleen architecture reorganization, partially restoring the distinct cellular components and their localization in the spleen. The results from this study indicate that DHEA and MET could play an important role in the restoration of both adaptive humoral and cellular immune response in LPS-immunosuppressed mice, reinforcing the concept of a central involvement of endogenous glucocorticoids on this phenomenon.

Dehydroepiandrosterone triggers autophagic cell death in human hepatoma cell line HepG2 via JNK-mediated p62/SQSTM1 expression

“…For instance, it is well documented that DHEA has beneficial effects in animal models of non-insulin-dependent diabetes mellitus due to both insulin sensitivity and secretion (3,4). DHEA has also an immune stimulatory potential mainly achieved through the stimulation of cytokines production from both myeloid and lymphoid cells (5,6). Interestingly, growing lines of evidence demonstrated chemopreventive and antiproliferative properties of DHEA both in vitro and in vivo (7).…”

Consequences of the Lack of IL-10 in Different Endotoxin Effects and its Relationship With Glucocorticoids

“…GC are strong inhibitors of proinflammatory mediators such as TNF-α, and are crucial agents in the refractoriness to LPS in tolerant WT mice (8,9,18). In order to investigate whether the absence of IL-10 exerts changes on the corticoid-mediated protection in the naive mice to a lethal dose of LPS, we evaluated the effect of a synthetic GC, Dexamethasone (DEX), in IL-10 KO compared to WT mice.…”

“…One important reason of this failure was the little attention paid to the development of compensatory anti-inflammatory response syndrome (CARS), a dynamic period that, frequently, concludes in a severe immunosuppression and where the majority of deaths occur (4,5). The resolution of inflammation, as well as the induction of immunosuppression involves intricate networks of effector cells and molecules, among which IL-10 and glucocorticoids (GC) are usually regarded as critical antiinflammatory agents (6)(7)(8)(9).. Interleukin-10 (IL-10), the canonical anti-inflammatory cytokine, has also been pointed out as a central mediator in the late phase of sepsis Around 50% of sepsis cases are associated to Gram-negative infections, where lipopolysaccharides (LPS; also known as endotoxins), a constituent of the bacterial outer membrane, have a central role throughout the development of the disease (10). While LPS initially induces an exacerbated production of pro-inflammatory cytokines leading to multiorgan failure and death resembling a septic shock, it is also capable of inducing endotoxin tolerance, an anti-inflammatory state that renders the host temporarily refractory to a subsequent lethal dose of LPS, which is the initial phase of the…”

Therapeutic interventions in sepsis: current and anticipated pharmacological agents

“…Primary, secondary and T-cell-mediated immune responses were restored with mifepristone (RU486), an antagonist of glucocorticoid receptors (Rearte et al, 2010). Other modulators of glucocorticoids, such as dehydroepiandrosterone, a hormone with anti-glucocorticoid properties, or metyrapone, an inhibitor of corticosterone synthesis, were able to partially, but significantly, restore the humoral immune response in immunosuppressed mice (Rearte et al, 2013). A significant recovery of splenocyte proliferation and restoration of distinct cellular components leading to reorganization of spleen architecture was also observed, resulting in restoration of the hypersensitivity response, with these treatments.…”