Salutary effects of 17 -estradiol on T-cell signaling and cytokine production after trauma-hemorrhage are mediated primarily via estrogen receptor-

Suzuki T, Shimizu T, Yu HP, Hsieh YC, Choudhry MA, Chaudry IH. Salutary effects of 17 -estradiol on T-cell signaling and cytokine production after trauma-hemorrhage are mediated primarily via estrogen receptor. Am J Physiol Cell Physiol 292: C2103–C2111, 2007. First published February 7, 2007; doi:10.1152/ajpcell.00488.2006.—Although 17 -estradiol (E2) administration following trauma-hemorrhage prevents the suppression in splenocyte cytokine production, it remains unknown whether the salutary effects of 17 -estradiol are mediated via estrogen receptor (ER)or ER. Moreover, it is unknown which signaling pathways are involved in 17 -estradiol’s salutary effects. Utilizing an ERor ER-specific agonist, we examined the role of ERand ERin E2-mediated restoration of T-cell cytokine production following trauma-hemorrhage. Moreover, since MAPK, NFB, and activator protein (AP)-1 are known to regulate T-cell cytokine production, we also examined the activation of MAPK, NFB, and AP-1. Male rats underwent trauma-hemorrhage (mean arterial pressure 40 mmHg for 90 min) and fluid resuscitation. ERagonist propyl pyrazole triol (PPT; 5 g/kg), ERagonist diarylpropionitrile (DPN; 5 g/kg), 17 -estradiol (50 g/kg), or vehicle (10% DMSO) was injected subcutaneously during resuscitation. Twenty-four hours thereafter, splenic T cells were isolated, and their IL-2 and IFNproduction and MAPK, NFB, and AP-1 activation were measured. T-cell IL-2 and IFNproduction was decreased following trauma-hemorrhage, and this was accompanied with a decrease in T-cell MAPK, NFB, and AP-1 activation. PPT or 17 -estradiol administration following trauma-hemorrhage normalized those parameters, while DPN administration had no effect. Since PPT, but not DPN, administration following trauma-hemorrhage was as effective as 17 -estradiol in preventing the T-cell suppression, it appears that ERplays a predominant role in mediating the salutary effects of 17 -estradiol on T cells following trauma-hemorrhage, and that such effects are likely mediated via normalization of MAPK, NFB, and AP-1 signaling pathways.