Differential effects of glucocorticoids in the establishment and maintenance of endotoxin tolerance

REARTE B, LANDONI V, LABORDE E, FERNÁNDEZ G, ISTURIZ MA

CLINICAL AND EXPERIMENTAL IMMUNOLOGY

WILEY-BLACKWELL PUBLISHING, INC

Año: 2010 vol. 159 p. 208 - 216

0009-9104

Gram-negative infections can result in endotoxic shock, which is the mostcommon cause of death in intensive care units.Most of the undesirable effectsin sepsis and septic shock have been ascribed to lipopolysaccharide (LPS), anormal constituent of the bacterial wall. The response to LPS involves rapidsecretion of proinflammatory cytokines [tumour necrosis factor-a, interleukin(IL)-1, IL-6, IL-8, interferon-g] and the concomitant induction of antiinflammatorymediators such as IL-10 and transforming growth factor-b andglucocorticoids (GC), which render the host temporarily refractory to subsequentlethal doses of LPS challenge in a process known as LPS or endotoxintolerance. Although protective from the development of sepsis or systemicinflammation, endotoxin tolerance has also been pointed out as the principalcause of the non-specific immunosuppression described in these patients. Inthis report we demonstrate, using a mouse model, that while the maintenanceof tolerance is dependent upon GC, the establishment of tolerance by LPScould be inhibited by dexamethasone (Dex), a synthetic GC. Conversely, wedemonstrated that mifepristone (RU486), a known GC receptor antagonist,was capable of inducing a transient and reversible disruption of endotoxintolerance, also permitting partial restoration of the humoral immuneresponse in LPS tolerant/immunosuppressed mice. These results are encouragingfor the management of immunosuppression in sepsis and/or noninfectiousshock, and deserve further investigation in the future.