Gender differences in liver IL-6R expression

描述（申请人提供）：人们认为酒精性肝损伤的主要原因是炎症，众所周知，女性比男性更容易患酒精性肝病（ALD）。虽然促炎细胞因子IL-6的循环水平升高是人类严重ALD的标志，但对其受体（IL-6R?）的表达及其在慢性酒精给药过程中的活性知之甚少。对大鼠的初步研究显示，酒精诱导的肝脏IL-6R?的RNA和蛋白质水平存在明显的性别差异。和我吗?灌胃乙醇喂养4周后B表达。研究发现，女性在摄入乙醇两周后，肝脏STATS磷酸化水平更高，而不是四周，这表明尽管受体表达增加，但信号活性却有所下降。相反，摄入乙醇的男性I？与女性相比，B的表达可能抑制IL-6R？表达式或功能考虑到炎症与乙醇诱导的肝损伤的关联，在本应用中，我们建议：1)确定睾酮或雌激素是否直接影响IL- 6R的表达？还是我?乙醇消耗动物肝脏中的B。为了实现这一点，我们打算使用慢性乙醇消耗的灌胃乙醇喂养模型。在乙醇暴露之前，切除卵巢的大鼠将皮下植入含有睾酮或雌激素的微渗透泵。肝组织病理学，有丝分裂，IL-6R？我呢？在乙醇暴露2周和4周后评估B mRNA和蛋白表达。2)判断IL-6R激活或过度刺激是否与肝损害相关。虽然初步数据表明IL-6R在雌性乙醇消耗动物中上调，但受体与肝损伤增加之间缺乏明确的联系。切除卵巢的大鼠每天注射重组IL-6R激动剂，为期四周的乙醇喂养。将评估肝脏组织病理学、循环肝酶和IL-6R信号转导分子。通过将乙醇消耗大鼠暴露于IL-6R激动剂，应该可以将损伤与受体激活联系起来。

DESCRIPTION (provided by applicant): It is thought that the major cause of alcohol-induced liver injury is inflammation, and it is well known that women are more susceptible to alcoholic liver disease (ALD) than men. While increased circulating levels of the proinflammatory cytokine IL-6 are a marker for serious ALD in humans, little is known about the expression of its receptor (IL-6R?) and its activity during chronic alcohol administration. Preliminary studies in rats show clear gender differences at both the RNA and protein levels of alcohol-induced liver IL-6R? and I?B expression after up to four weeks of intragastric ethanol feeding. Liver STATS phosphorylation was found to be higher in females after two, but not four weeks of ethanol consumption, indicating a loss of signaling activity in spite of increased receptor expression. Conversely, ethanol-consuming males displayed increased I?B expression as compared to females, which may inhibit IL-6R? expression or function. Given the association of inflammation with ethanol induced liver damage, in this application we propose to: 1) Determine whether testosterone or estrogen directly affect the expression of IL- 6R? or I?B in the liver of ethanol consuming animals. To accomplish this, we intend to use the intragastric ethanol-feeding model of chronic ethanol consumption. Prior to ethanol exposure, ovarectomized rats will be implanted with subcutaneous, vehicle, testosterone or estrogen containing micro-osmotic pumps. Liver histopathology, mitogenesis, IL-6R?, and I?B mRNA and protein expression will be assessed after two and four weeks of ethanol exposure. 2) Determine if there is a relationship between IL-6R activation or over-stimulation and liver damage. While preliminary data indicates that IL-6R is upregulated in female ethanol consuming animals, there lacks a definitive link between the receptor and increased liver damage. Ovarectomized rats will be treated with recombinant IL-6R agonists via injection daily, during four-week ethanol feeding. Liver histopathology, circulating liver enzymes, and IL-6R signal transducing molecules will be assessed. By exposing ethanol- consuming rats to IL-6R agonists, it should be possible to correlate damage with receptor activation.