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

Although 17 beta-estradiol (E2) administration following trauma-hemorrhage prevents the suppression in splenocyte cytokine production, it remains unknown whether the salutary effects of 17 beta-estradiol are mediated via estrogen receptor (ER)-alpha or ER-beta. Moreover, it is unknown which signaling pathways are involved in 17 beta-estradiol's salutary effects. Utilizing an ER-alpha- or ER-beta-specific agonist, we examined the role of ER-alpha and ER-beta in E2-mediated restoration of T-cell cytokine production following trauma-hemorrhage. Moreover, since MAPK, NF-kappa B, and activator protein (AP)-1 are known to regulate T-cell cytokine production, we also examined the activation of MAPK, NF-kappa B, and AP-1. Male rats underwent trauma-hemorrhage ( mean arterial pressure 40 mmHg for 90 min) and fluid resuscitation. ER-alpha agonist propyl pyrazole triol (PPT; 5 mu g/kg), ER-beta agonist diarylpropionitrile (DPN; 5 mu g/kg), 17 beta-estradiol (50 mu 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 IFN-gamma production and MAPK, NF-kappa B, and AP-1 activation were measured. T-cell IL-2 and IFN-gamma production was decreased following trauma-hemorrhage, and this was accompanied with a decrease in T-cell MAPK, NF-kappa B, and AP-1 activation. PPT or 17 beta-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 beta-estradiol in preventing the T-cell suppression, it appears that ER-alpha plays a predominant role in mediating the salutary effects of 17 beta-estradiol on T cells following trauma-hemorrhage, and that such effects are likely mediated via normalization of MAPK, NF-kappa B, and AP-1 signaling pathways.