Salutary effects of 17beta-estradiol on T-cell signaling and cytokine production after trauma-hemorrhage are mediated primarily via estrogen receptor-alpha.
Although 17beta-estradiol (E2) administration following trauma-hemorrhage prevents the suppression in splenocyte cytokine production, it remains unknown whether the salutary effects of 17beta-estradiol are mediated via estrogen receptor (ER)-alpha or ER-beta. Moreover, it is unknown which signaling pathways are involved in 17beta-estradiol's salutary effects. Utilizing an ER-alpha- or ER-beta-specific agonist, we examined the role of ER-alpha and ER-beta in E2-mediated restoration of T-cell cytokine production following trauma-hemorrhage. Moreover, since MAPK, NF-kappaB, and activator protein (AP)-1 are known to regulate T-cell cytokine production, we also examined the activation of MAPK, NF-kappaB, and AP-1. Male rats underwent trauma-hemorrhage (mean arterial pressure 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), 17beta-estradiol (50 microg/kg), or vehicle (10% DMSO) was injected subcutaneously during resuscitation. Twenty-four hours thereafter, splenic T cells were isolated, and their IL-2 and IFN-gamma production and MAPK, NF-kappaB, and AP-1 activation were measured. T-cell IL-2 and IFN-gamma production was decreased following trauma-hemorrhage, and this was accompanied with a decrease in T-cell MAPK, NF-kappaB, and AP-1 activation. PPT or 17beta-estradiol administration following trauma-hemorrhage normalized those parameters, while DPN administration had no effect. Since PPT, but not DPN, administration following trauma-hemorrhage was as effective as 17beta-estradiol in preventing the T-cell suppression, it appears that ER-alpha plays a predominant role in mediating the salutary effects of 17beta-estradiol on T cells following trauma-hemorrhage, and that such effects are likely mediated via normalization of MAPK, NF-kappaB, and AP-1 signaling pathways.
Suzuki
Takao
T
Center for Surgical Research and Dept. of Surgery, University of Alabama at Birmingham, AL 35294-0019, USA.
Shimizu
Tomoharu
T
Yu
Huang-Ping
HP
Hsieh
Ya-Ching
YC
Choudhry
Mashkoor A
MA
Chaudry
Irshad H
IH
D000818:Animals; D016207:Cytokines / Q000096:biosynthesis*; D004958:Estradiol / Q000378:metabolism / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005786:Gene Expression Regulation; D006470:Hemorrhage / Q000378:metabolism*; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D014947:Wounds and Injuries / Q000378:metabolism*
D016207:Cytokines; D047628:Estrogen Receptor alpha; D007376:Interleukin-2; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D004958:Estradiol; D007371:Interferon-gamma; D020928:Mitogen-Activated Protein Kinases