Center for Surgical Research and Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama 35294-0019, USA.
J Cell Physiol. 2011 Jan;226(1):205-11. doi: 10.1002/jcp.22327.
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.
研究表明，给予 17β-雌二醇可预防创伤-出血引起的库普弗细胞产生促炎细胞因子增加和相关的多器官损伤。由于在缺血条件下激活过氧化物酶体增殖物激活受体 γ（PPARγ）已被证明具有保护作用，因此我们研究了 PPARγ 是否在创伤-出血后 17β-雌二醇对库普弗细胞细胞因子产生的有益作用中发挥作用。雄性小鼠接受创伤-出血（平均血压 40mmHg 持续 90 分钟，然后复苏）。在复苏中期，通过皮下注射 17β-雌二醇（50µg/kg）或载体加或不加 PPARγ拮抗剂 GW9662。在创伤-出血后 2 小时，测定血浆白细胞介素（IL）-6 和肿瘤坏死因子（TNF）-α 水平、库普弗细胞 IL-6 和 TNF-α 产生和 mRNA 表达以及 PPARγ、核因子（NF）-κB 和激活蛋白（AP）-1 DNA 结合活性。创伤-出血后，库普弗细胞 IL-6 和 TNF-α 产生以及血浆 IL-6 和 TNF-α 水平增加。此外，在这种情况下 NF-κB 和 AP-1 DNA 结合活性以及 IL-6 和 TNF-α mRNA 表达也增强。然而，17β-雌二醇的给予使所有这些参数正常化。尽管创伤-出血后 PPARγ 活性降低，但创伤-出血后给予 17β-雌二醇可使 PPARγ 活性升高至正常水平以上。然而，通过共同给予 GW9662 抑制 PPARγ 可消除 17β-雌二醇对血浆细胞因子和库普弗细胞的有益作用。因此，PPARγ 的激活似乎在介导 17β-雌二醇对创伤-出血后血浆细胞因子水平和库普弗细胞细胞因子产生的有益作用中起重要作用，这可能是通过 NF-κB 和 AP-1 介导的。
