Abstract
Although 17β‐estradiol (E2) attenuates the alterations in Kupffer cells and splenic macrophages (MΦ) cytokine production following trauma‐hemorrhage, the mechanism by which this occurs remains unknown. Utilizing a cell‐impermeable E2 conjugated with BSA (E2‐BSA), we examined the non‐genomic effects of E2 on the above two cell population cytokine production, MAPK and transcription factors activation following trauma‐hemorrhage. Male Sprague–Dawley rats underwent trauma‐hemorrhage (mean BP 40 mmHg for 90 min, then resuscitation). E2, E2‐BSA (1 mg/kg E2) with or without an estrogen receptor antagonist (ICI 182,780), or vehicle was administrated during resuscitation. Two hrs thereafter, Kupffer cells and SMΦ production of IL‐6, TNF‐α, and IL‐10, activation of MAPK (p38, ERK‐1/2, and JNK), and transcription factors (NF‐κB and AP‐1) were determined. IL‐6, TNF‐α, and IL‐10 productive capacity, MAPK, and transcription factors activation increased in Kupffer cells while they decreased in SMΦ following trauma‐hemorrhage. However, E2 administration normalized all of these alterations. Although E2‐BSA also attenuated the alterations in cytokine production/transcription factors, the values were higher in Kupffer cells and lower in SMΦ compared to shams. In contrast, E2‐BSA prevented trauma‐hemorrhage‐mediated changes in MAPK activation to the same extent as E2. Co‐administration of ICI 182,780 abolished E2‐BSA effects. Although some MAPK inhibitors suppressed cytokine production, the inhibitor effectiveness was dependent on cytokine, cell type and animal condition (trauma‐hemorrhage or sham). Thus, E2 effects on Kupffer cells and SMΦ cytokine production and transcription factors activation following trauma‐hemorrhage are mediated at least in part via non‐genomic pathway and these non‐genomic effects are likely mediated via MAPK pathways. J. Cell. Physiol. 214: 662–672, 2008. © 2007 Wiley‐Liss, Inc.