EXERCISE AS A MEANS OF ENHANCING IMMUNITY IN THE AGED

锻炼是增强老年人免疫力的一种手段

基本信息

批准号：
6362215
负责人：
JEFFREY Adam WOODS
金额：
$ 11.18万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-04-04 至 2003-02-28
项目状态：
已结题

项目摘要

Macrophage (Mphi) responsiveness to activating signals like interferon- gamma (IFN-gamma), lipopolysaccharide (LPS), and Propionibacterium acnes (p. Acnes) declines with age in human and animals as assessed by decreased anti-tumor activity, and nitric oxide (NO), H2O, and tumor necrosis factor-alpha (TNF-alpha) production. Recent epidemiological evidence suggests that chronic exercise can protect against cancer and infectious disease. In young mice, we have shown that exercise increases murine Mphi anti-tumor activity medicated by increased TNF- alpha and NO production and perhaps increased sensitivity to IFN- gamma. Growth hormone (GH) and PRL (PRL) can increase Mphi function and it is likely that GH deficiency contributes to Mphi dysregulation in the aged. Unfortunately, the extent to which chronic exercise, which increases GA and PRL and attenuates glucocorticoid (CORT) secretion and sensitivity, affects depressed Mphi function in the aged is unknown. We hypothesize that chronic exercise will reverse the age-related decrease in Mphi function by increasing the GH/PRL: CORT ratio and decreasing Mphi sensitivity to CORT. We will test this hypothesis by chronically (16 was) exercising young (6 month), mature (12 month), and senescent (24 month) Balb/cByJNia mice in experiments designed to answer the following critical questions; (1) Does chronic exercise increase Mphi function and responsiveness to classical activating signals in aged mice as it does in young mice. We will inject P. Acnes in vivo and culture thioglycollate (TG)-elicited peritoneal Mphi's with IFN-gamma and LPS in vitro to determine the role of chronic exercise in Mphi priming and activation for anti-tumor activity, MHC II expression, and effector molecule production. We will explore potential mechanisms for this effect by measuring Mphi IFN-gamma and LPS (CD14) receptor density and signaling through mitogen activated protein kinases (MAPK's). We will also measure P. acnes-induced IFN-gamma production. (2) Is the exercise induced increase in Mphi function due to an increase in the GH/PRL:CORT ration and decreased Mphi CORT sensitivity? In vivo, we will address this by treating aged mice with bromocriptine (a dopamine agonist that suppresses PRL), and octreotide (somatostatin analog that inhibits GH). In vitro TG-elicited Mphi'S will be incubated with varying concentrations of IFN-gamma. And effector molecule production assays. Mechanism will be determined by measuring Mphi CORT receptor number and affinity and CORT induced expression of the NfkappaB antagonist IkappaB. Lastly, (3) Can GH an dPRL substitute for, or synergize with IFN-gamma, in priming Mphi's for activation by LPS in aged mice for activation. We will prime TG- elicited Mphi's from exercised mice of different ages with GH, PRL, and IFN-gamma activate them with LPS and measure anti-tumor activity and effector molecule production. We believe that GH and PRL and prime Mphi's from aged mice for activation. We will explore the mechanism for this effect by GH/PRL receptor and MAPK blockade and measurement of MAPK activity. These experiments will be the first to describe and mechanistically address how chronic exercise affects the aging immune system in an attempt to explore the potential use of exercise in enhancing age-associated declines in immune infection.

巨噬细胞（MPHI）对激活信号（例如干扰素）的反应性伽马（IFN-GAMMA），脂多糖（LPS）和丙片杆菌痤疮（痤疮）随着人类和动物的年龄而下降，如抗肿瘤活性降低，一氧化氮（NO），H2O和肿瘤坏死因子-Alpha（TNF-Alpha）产生。最近的流行病学有证据表明，慢性运动可以预防癌症和传染病。在年轻的老鼠中，我们已经表明了运动增加鼠类MPHI抗肿瘤活性，通过增加TNF- alpha，没有生产，也许会增加对IFN-的敏感性伽玛。生长激素（GH）和PRL（PRL）可以增加MPHI 功能，GH缺乏症可能有助于MPHI 老年人的失调。不幸的是，慢性的程度运动，增加了GA和PRL并减弱糖皮质激素（cort）分泌和敏感性会影响MPHI抑郁症的功能老化是未知的。我们假设慢性运动将逆转通过增加GH/PRL：CORT，与年龄相关的MPHI功能降低比率和降低MPHI对Cort的敏感性。我们将测试这个长期（16岁）锻炼年轻（6个月）的假设，成熟（12个月）和实验中的BALB/CBYJNIA小鼠（24个月）BALB/CBYJNIA小鼠旨在回答以下关键问题；（1）慢性运动增加了MPHI功能和对经典激活的响应能力年龄小鼠的信号和年轻小鼠一样。我们将注入痤疮P. 体内和培养硫糖酸酯（TG） - 腹膜mphi的腹膜体外IFN-GAMMA和LPS确定慢性运动的作用在MPHI启动和抗肿瘤活性的激活中，MHC II 表达和效应分子产生。我们将探索潜力通过测量MPHI IFN-GAMMA和LPS的机制（CD14）通过有丝分裂原活化蛋白的受体密度和信号传导激酶（MAPK）。我们还将测量痤疮疟原虫诱导的IFN-gamma 生产。（2）是练习引起的MPHI功能到期的增加增加了GH/PRL：Cort评分和Mphi Cort的降低灵敏度？在体内，我们将通过用溴o不般的（一种抑制PRL的多巴胺激动剂）和奥曲肽（抑制GH的生长抑素类似物）。体外TG引用的MPHI意志与不同浓度的IFN-gamma一起孵育。和效应器分子生产分析。机制将由测量Mphi Cort受体数量，亲和力和Cort诱导 nfkappab拮抗剂ikappab的表达。最后，（3）可以 dprl在启动mphi中代替或与ifn-gamma协同用于LPS在老年小鼠中激活以激活。我们将为TG- 通过使用GH，PRL的不同年龄的小鼠引起MPHI IFN-gamma用LPS激活它们并测量抗肿瘤活性和效应分子的产生。我们相信GH和PRL以及来自老年小鼠的Prime Mphi用于激活。我们将探索 GH/PRL受体和MAPK封锁和MAPK封锁的机制以及 MAPK活动的测量。这些实验将是第一个描述并机械地解决慢性运动如何影响衰老免疫系统试图探索潜在的使用在增强免疫感染中与年龄相关的下降方面的运动。