Are the protective effects of 17β‐estradiol on splenic macrophages and splenocytes after trauma‐hemorrhage mediated via estrogen‐receptor (ER)‐α or ER‐β?

The depression in cell‐mediated immune function following trauma‐hemorrhage is shown to be restored by 17β‐estradiol (E2) administration. However, it remains unknown which of the two estrogen‐receptors, (ER)‐α or ER‐β, plays the predominant role in mediating the beneficial effects of E2. Female B57BL/J6 ER‐β −/− transgenic mice [knockout (KO)] and corresponding ovariectomized wild‐type (WT) mice were subjected to laparotomy and hemorrhagic shock (35.0±5.0 mmHg for 90 min) and treated with E2 (50 μg/25 g) or ER‐α agonist propyl pyrazole triol (PPT; 50 μg/25 g) following trauma‐hemorrhage. Four hours after resuscitation, systemic cytokine concentrations and cytokine release by splenocytes and splenic macrophages were determined by cytometric bead array. Trauma‐hemorrhage resulted in a significant increase in plasma tumor necrosis factor α (TNF‐α), interleukin (IL)‐6, and IL‐10. In contrast, the release of these cytokines by splenic macrophages was decreased significantly in WT and KO animals. Administration of E2 or PPT following trauma‐hemorrhage produced a significant reduction in systemic TNF‐α and IL‐6 concentrations in WT and KO mice. Although the suppression in the productive capacity of these cytokines following trauma‐hemorrhage by macrophages and splenocyte was also prevented in E2‐ and PPT‐treated WT mice, the release of cytokines by macrophages and splenocytes in E2‐ and PPT‐treated KO mice was not restored to the levels observed in sham animals. These findings collectively suggest that both receptors appear to play a significant role in mediating the immunoprotective effects of E2 in different tissue compartments following trauma‐hemorrhage.