PSYCHOSOCIAL STRESS-INDUCED FEVER--ROLE OF CYTOKINES

暴露在心理社会压力下会导致AS患者体温升高 老鼠体内的温度高达2摄氏度。中国人的体温上升 对心理压力的反应也有报道。心理社会 压力也被证明可以改变艾滋病的进程。在过去的时间里 几年来，我们已经产生的数据支持这样的假设 应激性“体温过高”实际上是一种发烧(即 体温调节设定值)，由内源性热原和 前列腺素E2。此外，我们已经证明，简单地将老鼠暴露在 一种新的环境导致血浆显著增加 炎症和免疫介质IL-6的浓度，以及 用抗肿瘤坏死因子抗血清(即肿瘤坏死因子α)预处理大鼠可导致 应激热的增加。我们感兴趣的假设是 被认为与感染有关的细胞因子和其他多肽- 诱导发烧(既能引起发烧，又能调节 发热)(如IL-1、TNF、IL-6、PGE2、精氨酸加压素(AVP)和α- MSH)是应激所致体温升高的原因 不是由内源性阿片类药物引起的。 拟议研究的具体目标如下： 1.继续研究接触小说的影响 环境(大鼠)对血浆IL-6、PGE2、Arg活性的影响 加压素和α-MSH。 2.测定血浆IL-6、IL-1、肿瘤坏死因子、前列腺素E_2、精氨酸加压素、 和α-MSH高到足以影响(增加或减少) 压力引起的温度升高。 3.检验心理压力会导致心理压力释放的假设 IL-1、TNF、IL-6、PGE2、AVP和α-MSH进入脑脊液，或 大鼠的脑组织。 4.检验心理应激导致心理焦虑的假说 库普弗细胞或循环自发释放IL-1、TNF或IL-6 应激后分离的血单核细胞。 5.检验心理压力使库普弗细胞或 循环血单核细胞对其他刺激更敏感，如 脂多糖，已知引起IL-1，肿瘤坏死因子， 和IL-6。 6.检验抗体或抗体预处理大鼠的假设 抗IL-1、TNF、IL-6、AVP和α-MSH的特异性受体拮抗剂 改变(或增加或减少)压力诱导的体温过高。 这些研究可能对了解艾滋病的发展具有相关性。 自另一项研究以来，从潜伏的艾滋病毒感染到全面的疾病 实验室研究表明，IL-6和肿瘤坏死因子具有协同诱导作用 HIV在慢性HIV感染细胞模型中的表达。

Exposure to psychosocial stress produces rises in body temperature of as much as 2 degrees Celsius in rats. Rises in body temperature of people in response to psychological stress have also been reported. Psychosocial stress has also been shown to alter the course of AIDS. Over the past several years we have generated data that support the hypothesis that stress "hyperthermia" is actually a fever (i.e., an elevation in thermoregulatory set-point), caused by endogenous pyrogens and prostaglandin E2. In addition, we have shown that simply exposing a rat to a novel environment results in a significant increase in the plasma concentration of IL-6, a mediator of inflammation and immunity, and that pretreatment of rats with antiserum to TNF (i.e., TNFalpha) results in an increase in stress-fevers. The hypothesis we are interested in testing is that cytokines and other peptides thought to be involved in infection- induced fever (both in inducing fever and modulating the magnitude of the fever) (e.g., IL-1, TNF, IL-6, PGE2 arginine vasopressin (AVP) and alpha- MSH) are responsible for that portion of stress-induced hyperthermia that is not caused by endogenous opioids. The specific aims of the proposed studies are as follows: 1. To continue our investigations on the effects of exposure to a novel environment (in rats) on plasma activity of IL-6, PGE2, arginine vasopressin, and alpha-MSH. 2. To determine whether plasma activities of IL-6, IL-1, TNF, PGE2, AVP, and alpha-MSH are high enough to affect (either increases or decreases) the stress-induced rise in temperature. 3. To test the hypothesis that psychological stress induces the release of IL-1, TNF, IL-6, PGE2, AVP, and alpha-MSH into the cerebrospinal fluid, or brain tissue of rats. 4. To test the hypothesis that psychological stress induces the spontaneous release of IL-1, TNF, or IL-6 from Kupffer cells or circulating blood monocytes isolated following the stress. 5. To test the hypothesis that psychological stress makes Kupffer cells or circulating blood monocytes more sensitive to other stimuli, such as lipopolysaccharide, known to cause the synthesis and release of IL-1, TNF, and IL-6. 6. To test the hypothesis that pretreatment of rats with antibodies or specific receptor antagonists against IL-1, TNF, IL-6, AVP, and alpha-MSH alters (either increases or decreases) stress-induced hyperthermia. These studies may have relevance for understanding the progression of AIDS from latent HIV infection to full-blown disease since studies from another laboratory have shown that IL-6 and TNF results in a synergistic induction of HIV expression in chronically HIV-infected cell models.