Effect Of Glucocorticoids In The Development Of Endotoxin Tolerance

REARTE B; LANDONI V.I; CHIARELLA P; LABORDE E; LOPEZ M.F; FERNANDEZ G.C; ISTURIZ M.A

Rio de Janeiro Brasil

Congreso; 13th International Congress of Immunology, Rio de Janeiro, Brazil; 2007

Effect of Glucocorticoids in the Development     of Endotoxin  Tolerance Bárbara Rearte, Verónica Landoni, Paula Chiarella, Evangelina Laborde, María Florencia López, Gabriela C. Fernández, Martín A. Isturiz. Systemic inflammatory phenomena, usually called SIRS (sepsis, hemorrhagic, traumatic shock, etc.), are consequence of the exposure to different stimuli that induce proinflammatory cytokines release.  This situation is rapidly compensated by a sudden increase of antiinflammatory cytokines that frequently, conclude in an immunosuppression state. Sepsis is, perhaps, the most relevant SIRS and more of 50% of the sepsis are due to infections by gram negative bacteria.  LPS, the outer membrane components of these bacteria, are the causal agents of the systemic proinflammatory phase, and could be involved in the immunosuppression state observed in late sepsis. LPS tolerance phenomenon, one of the most relevant events in sepsis, is defined by a host reduced capacity to produce proinflammatory cytokines after previous LPS exposure. The comprehension of mechanisms underlying the LPS tolerance phenomenon is very important since they could be involved in the immunosuppression observed in sepsis, which is one of the most important causes of high mortality in patients. The aim of this work was to study some aspects related to LPS tolerance involved-mechanisms.  Thus, using in vivo and in vitro models we analyzed the effects of glucocorticoids and some cytokines in two different phases of this phenomenon.  In the initial phase, or tolerance establishment, we evaluated the role of dexamethasone and TNF-α.  In the second one, or tolerance maintenance, we studied the role of IFN-g  and a competitive inhibitor of glucocorticoids actions, RU486. LPS Tolerance is one of the most relevant events in the pathophysiology of gram negative-bacteria-induced sepsis. This phenomenon essentially consists in two well differentiated phases, as follows: a) the establishment; b) the maintenance. The comprehension of this process is still under study since tolerance seems to be one of the singnificant mechanisms involved in immunosuppression in sepsis. Ru486 disrupts the phenomenon of in vivo tolerance in a transient manner opening a temporary window to LPS proinflammatory action.  In fact, after 3 hr of RU486 injection the system returns to the original refractory status, suggesting that RU486 action has not modified the mechanisms involved in the generation of the tolerant state. These results indicate that glucocorticoids are involved in the maintenance of in vivo tolerance.  This is consistent with the fact that naïve mice treated with dexamethasone are refractory to a LPS lethal dose. However, when LPS and dexamethasone are injected simultaneously, during the process of tolerization, the tolerance mechanism cannot be established. When RU486 is injected instead of dexamethasone, LPS tolerance is normally established. In brief, these results indicate that glucocorticoids could play a dual role since they are important in the maintenance of in vivo tolerance while they are not involved in the establishment of LPS in vivo tolerance. Preliminary results indicate that the presence of TNF-α is not necessary for the establishment of LPS tolerance. (in vitro). Similar effects to that obtained with RU486 in the transient disruption of tolerance have also been observed (in vitro) using IFN-g. Similarly to RU486, IFN-g has not altered the mechanisms involved in the establishment of LPS tolerance.