Dantzer Robert, Kelley Keith W
Integrative Immunology and Behavior Program, Laboratory of Integrative Immunophysiology, Department of Animal Sciences, University of Illinois at Urbana-Champaign, IL 61801, USA.
Brain Behav Immun. 2007 Feb;21(2):153-60. doi: 10.1016/j.bbi.2006.09.006. Epub 2006 Nov 7.
Cytokine-induced sickness behavior was recognized within a few years of the cloning and expression of interferon-alpha, IL-1 and IL-2, which occurred around the time that the first issue of Brain, Behavior, and Immunity was published in 1987. Phase I clinical trials established that injection of recombinant cytokines into cancer patients led to a variety of psychological disturbances. It was subsequently shown that physiological concentrations of proinflammatory cytokines that occur after infection act in the brain to induce common symptoms of sickness, such as loss of appetite, sleepiness, withdrawal from normal social activities, fever, aching joints and fatigue. This syndrome was defined as sickness behavior and is now recognized to be part of a motivational system that reorganizes the organism's priorities to facilitate recovery from the infection. Cytokines convey to the brain that an infection has occurred in the periphery, and this action of cytokines can occur via the traditional endocrine route via the blood or by direct neural transmission via the afferent vagus nerve. The finding that sickness behavior occurs in all mammals and birds indicates that communication between the immune system and brain has been evolutionarily conserved and forms an important physiological adaptive response that favors survival of the organism during infections. The fact that cytokines act in the brain to induce physiological adaptations that promote survival has led to the hypothesis that inappropriate, prolonged activation of the innate immune system may be involved in a number of pathological disturbances in the brain, ranging from Alzheimer's disease to stroke. Conversely, the newly-defined role of cytokines in a wide variety of systemic co-morbid conditions, ranging from chronic heart failure to obesity, may begin to explain changes in the mental state of these subjects. Indeed, the newest findings of cytokine actions in the brain offer some of the first clues about the pathophysiology of certain mental health disorders, including depression. The time is ripe to begin to move these fundamental discoveries in mice to man and some of the pharmacological tools are already available to antagonize the detrimental actions of cytokines.
细胞因子诱导的疾病行为在干扰素-α、白细胞介素-1和白细胞介素-2克隆和表达后的几年内被认识到，这些事件大约发生在1987年《脑、行为和免疫》第一期出版之时。一期临床试验证实，向癌症患者注射重组细胞因子会导致多种心理障碍。随后发现，感染后出现的促炎细胞因子生理浓度会作用于大脑，引发常见的疾病症状，如食欲不振、嗜睡、退出正常社交活动、发热、关节疼痛和疲劳。这种综合征被定义为疾病行为，现在被认为是动机系统的一部分，该系统会重新调整机体的优先事项，以促进从感染中恢复。细胞因子向大脑传达外周发生了感染，细胞因子的这种作用可以通过血液经传统内分泌途径发生，也可以通过传入迷走神经经直接神经传递发生。疾病行为在所有哺乳动物和鸟类中都会出现这一发现表明，免疫系统和大脑之间的通信在进化过程中得以保留，形成了一种重要的生理适应性反应，有利于机体在感染期间存活。细胞因子在大脑中发挥作用以诱导促进生存的生理适应这一事实，引发了这样一种假说，即先天免疫系统的不适当、长期激活可能与大脑中的多种病理障碍有关，从阿尔茨海默病到中风。相反，细胞因子在从慢性心力衰竭到肥胖等多种全身性共病中的新定义作用，可能开始解释这些患者精神状态的变化。事实上，细胞因子在大脑中作用的最新发现为某些心理健康障碍（包括抑郁症）的病理生理学提供了一些初步线索。将这些在小鼠身上的基础发现应用于人类的时机已经成熟，并且已经有一些药理学工具可用于拮抗细胞因子的有害作用。
