Mifepristone (RU486) restores humoral and T cell-mediated immune response in endotoxin immunosuppressed mice

REARTE BARBARA; ANDREA MAGLIOCO; LUCIANA BALBOA; BRUZZO J; LANDONI V; LABORDE E; PAULA CHIARELLA; RUGGIERO, R; GABRIELA FERNÁNDEZ; MARTÍN A. ISTURIZ

CLINICAL AND EXPERIMENTAL IMMUNOLOGY

WILEY-BLACKWELL PUBLISHING, INC

Año: 2010 p. 568 - 577

0009-9104

Sepsis and septic shock can be caused by Gram-positive and -negative bacteriaand other microorganisms. In the case of Gram-negative bacteria, endotoxin,a normal constituent of the bacterial wall, also known as lipopolysaccharide(LPS), has been considered as one of the principal agents causing the undesirableeffects in this critical illness. The response to LPS involves a rapidsecretion of proinflammatory cytokines such as tumour necrosis factor(TNF)-a, interleukin (IL)-1, IL-6, interferon (IFN)-g and the concomitantinduction of anti-inflammatory mediators such as IL-10, transforminggrowth factor (TGF)-b or glucocorticoids, which render the host temporarilyrefractory to subsequent lethal doses of LPS challenge in a process known asLPS or endotoxin tolerance. Although protective from the development ofsepsis or systemic inflammation, endotoxin tolerance has also been pointedout as the main cause of the non-specific humoral and cellular immunosuppressiondescribed in these patients. In this report we demonstrate, using amouse model, that mifepristone (RU486), a known glucocorticoid receptorantagonist, could play an important role in the restoration of both adaptivehumoral and cellular immune response in LPS immunosuppressed mice, suggestingthe involvement of endogenous glucocorticoids in this phenomenon.On the other hand, using cyclophosphamide and gemcitabine, wedemonstrated that regulatory/suppressor CD4+CD25+forkhead boxP3+ andGR-1+CD11b+ cells do not play a major role in the establishment or themaintenance of endotoxin tolerance, a central mechanism for inducing animmunosuppression state.