17 beta-estradiol administration following trauma-hemorrhage prevents the increase in Kupffer cell cytokine production and MAPK activation predominately via estrogen receptor-alpha.
BACKGROUND
17 beta-estradiol (E2) administration following trauma-hemorrhage (T-H) attenuates the elevation in plasma cytokines and Kupffer cell (KC) cytokine production; however, it remains unknown whether the salutary effects are mediated via estrogen receptor (ER)-alpha or ER-beta. We hypothesized that E2 mediates its salutary effects via ER-alpha and normalization of MAPK under those conditions.


METHODS
Male rats underwent T-H (mean blood pressure [BP] 40 mmHg for 90 min) and fluid resuscitation. ER-alpha agonist propyl pyrazole triol (PPT; 5 microg/kg), ER-beta agonist diarylpropionitrile (DPN; 5 microg/kg), E2 (50 microg/kg), or vehicle (10% DMSO) was injected subcutaneously during resuscitation. Twenty-four hours thereafter, KCs were isolated and their cytokine production (IL-6, TNF-alpha, IL-10) and MAPK activation were measured.


RESULTS
Cytokine production increased after T-H, however, PPT or E2 administration after T-H normalized KC cytokine production. Although DPN attenuated increased production of these cytokines, KC capacity to produce the cytokines remained significantly higher than sham. PPT or E2 also prevented T-H-mediated activation of MAPK in KC. However, DPN did not prevent MAPK activation.


CONCLUSIONS
Since PPT administration after T-H was more effective in decreasing KC cytokine production and MAPK activation than DPN, the salutary effects of E2 on KC functions are mediated predominantly via ER-alpha and normalization of MAPK following T-H.
Suzuki
Takao
T
Center for Surgical Research and Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35294-0019, USA.
Shimizu
Tomoharu
T
Yu
Huang-Ping
HP
Hsieh
Ya-Ching
YC
Choudhry
Mashkoor A
MA
Bland
Kirby I
KI
Chaudry
Irshad H
IH
D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D004958:Estradiol / Q000494:pharmacology*; D006470:Hemorrhage / Q000378:metabolism*; D007728:Kupffer Cells / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D010636:Phenols; D011422:Propionates / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000819:agonists / Q000378:metabolism*; D014950:Wounds, Penetrating / Q000378:metabolism*
C486182:2,3-bis(4-hydroxyphenyl)-propionitrile; D016207:Cytokines; D009570:Nitriles; D010636:Phenols; D011422:Propionates; D011720:Pyrazoles; D011960:Receptors, Estrogen; C486184:4,4',4''-(4-propyl-((1)H)-pyrazole-1,3,5-triyl) tris-phenol; D004958:Estradiol; D020928:Mitogen-Activated Protein Kinases