Role of PPARγ in the salutary effects of 17β-estradiol on Kupffer cell cytokine production following trauma-hemorrhage.
Studies have shown that administration of 17β-estradiol prevents trauma-hemorrhage-induced increase in proinflammatory cytokine production by Kupffer cells and associated multiple organ injury. Since activation of peroxisome proliferator-activated receptor γ (PPARγ) following ischemic conditions has been shown to be protective, we examined if PPARγ plays any role in the salutary effects of 17β-estradiol on Kupffer cell cytokine production following trauma-hemorrhage. Male mice underwent trauma-hemorrhage (mean blood pressure 40 mmHg for 90 min, then resuscitation). 17β-estradiol (50 µg/kg) or vehicle with or without PPARγ antagonist GW9662 was injected subcutaneously at the middle of resuscitation. At 2 h after trauma-hemorrhage, plasma interleukin (IL)-6 and tumor necrosis factor (TNF)-α levels, Kupffer cell IL-6 and TNF-α production and mRNA expression, and PPARγ, nuclear factor (NF)-κB and activator protein (AP)-1 DNA binding activity were determined. Kupffer cell IL-6 and TNF-α production, as well as plasma IL-6 and TNF-α levels, increased following trauma-hemorrhage. Moreover, NF-κB and AP-1 DNA binding activity and IL-6 and TNF-α mRNA expression were also enhanced under such conditions. However, 17β-estradiol administration normalized all these parameters. Although PPARγ activity decreased after trauma-hemorrhage, administration of 17β-estradiol following trauma-hemorrhage elevated PPARγ activity above the normal level. Inhibition of PPARγ by co-administration of GW9662, however, abolished the salutary effects of 17β-estradiol on plasma cytokine and Kupffer cells. Thus, activation of PPARγ appears to play an important role in mediating the salutary effects of 17β-estradiol on plasma cytokine levels and Kupffer cell cytokine production after trauma-hemorrhage, which are likely mediated via NF-κB and AP-1.
Suzuki
Takao
T
Center for Surgical Research and Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama 35294-0019, USA.
Kawasaki
Takashi
T
Choudhry
Mashkoor A
MA
Chaudry
Irshad H
IH
D000813:Anilides / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology*; D005786:Gene Expression Regulation; D006470:Hemorrhage / Q000378:metabolism*; D007728:Kupffer Cells / Q000378:metabolism*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014947:Wounds and Injuries / Q000378:metabolism
C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D016207:Cytokines; D047495:PPAR gamma; D012333:RNA, Messenger; D004958:Estradiol