Estrogen receptor-α predominantly mediates the salutary effects of 17β-estradiol on splenic macrophages following trauma-hemorrhage

Abstract

Although 17beta-estradiol administration following trauma-hemorrhage prevents the suppression in splenic macrophage cytokine production, it remains unknown whether the salutary effects are mediated via estrogen receptor (ER)-alpha or ER-beta and which signaling pathways are involved in such 17beta-estradiol effects. Utilizing ER-alpha- or ER-beta-specific agonists, this study examined the role of ER-alpha and ER-beta in 17beta-estradiol-mediated restoration of macrophage cytokine production following trauma-hemorrhage. In addition, since MAPK and NF-kappaB are known to regulate macrophage cytokine production, we also examined the activation of those signaling molecules. Male rats underwent trauma-hemorrhage (mean arterial pressure of 40 mmHg for 90 min) and fluid resuscitation. The ER-alpha agonist propyl pyrazole triol (PPT; 5 microg/kg), the ER-beta agonist diarylpropionitrile (DPN; 5 microg/kg), 17beta-estradiol (50 microg/kg), or vehicle (10% DMSO) was injected subcutaneously during resuscitation. Twenty-four hours thereafter, splenic macrophages were isolated, and their IL-6 and TNF-alpha production and activation of MAPK and NF-kappaB were measured. Macrophage IL-6 and TNF-alpha production and MAPK activation were decreased, whereas NF-kappaB activity was increased, following trauma-hemorrhage. PPT or 17beta-estradiol administration after trauma-hemorrhage normalized those parameters. DPN administration, on the other hand, did not normalize the above parameters. Since PPT but not DPN administration following trauma-hemorrhage was as effective as 17beta-estradiol in preventing the suppression in macrophage cytokine production, it appears that ER-alpha plays the predominant role in mediating the salutary effects of 17beta-estradiol on macrophage cytokine production following trauma-hemorrhage and that such effects are likely mediated via normalization of MAPK but not NF-kappaB signaling pathways.