Gender differences in liver IL-6R expression

描述(申请人提供)：据认为，酒精性肝脏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？)的表达知之甚少。以及它在长期饮酒期间的活动。对大鼠的初步研究表明，在酒精诱导的肝脏IL-6R？乙醇灌胃4周后，I？B蛋白表达增强。女性在饮用酒精两周后，肝脏STATS的磷酸化水平较高，但不是四周，这表明尽管受体表达增加，但信号活性丧失。相反，饮酒的男性表现出比女性更高的I？B表达，这可能是抑制IL-6R？表情或功能。鉴于炎症与酒精性肝损伤的相关性，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？或酒精摄入动物肝脏中的I？B。为了做到这一点，我们打算使用慢性酒精消费的胃内酒精喂养模型。在酒精暴露之前，去卵巢的大鼠将被植入皮下、赋形剂、睾酮或含有微渗泵的雌激素。在酒精暴露2周和4周后，将对肝脏组织病理学、有丝分裂、IL-6Rβ和I？b基因和蛋白的表达进行评估。2)确定IL-6R激活或过度刺激是否与肝损伤有关。虽然初步数据表明，IL-6R在雌性乙醇消费动物中上调，但该受体与肝脏损伤增加之间缺乏明确的联系。去卵巢的大鼠在四周的酒精喂养过程中，每天注射重组IL-6R激动剂。将评估肝脏组织病理学、循环肝酶和IL-6R信号转导分子。通过将饮用酒精的大鼠暴露于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.