Although 17beta-estradiol (E2) attenuates the alterations in Kupffer cells and splenic macrophages (MPhi)
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 SMPhi production of
IL-6,
TNF-alpha, and
IL-10, activation of
MAPK (p38, ERK-1/2, and JNK), and
transcription factors (NF-kappaB and AP-1) were determined.
IL-6,
TNF-alpha, and
IL-10 productive capacity, MAPK, and
transcription factors activation increased in Kupffer cells while they decreased in SMPhi 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 SMPhi 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 SMPhi
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.