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.