Twenty years of research on cytokine-induced sickness behavior

Abstract

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.

Figure 1

Psychological and pharmacological roots of the concept of sickness behavior. In behavioral sciences, the ability of animals to relate sickness and malaise to the nature of the nutrients they ingest was studied within the context of the conditioned taste aversion paradigm. This ability was further elaborated in terms of advantages during evolution and cognitive abilities. Some pharmacologists used the conditioned taste aversion paradigm for studying the aversive stimulus properties of drugs. However, this type of approach was miniscule when compared to the huge scientific and industrial investment in the systematic study of the stimulating properties of psychoactive drugs based on operant conditioning technology. The sickness-inducing properties of certain treatments were mainly quantified indirectly, via the disruption of natural or learned behavior. These two different lines of research, especially the last one, gave rise to the methodology currently used for studying cytokine-induced sickness behavior.

Figure 2

Evolution of the concept of sickness behavior. This figure illustrates the different steps in formulation of the concept of cytokine-induced sickness behavior. It demonstrates that the concept was grounded initially in two different lines of research that focused on the possible aversive stimulus properties of immune activation on one hand and the metabolic constraints of the fever response on the other hand. Ultimately, the concept of cytokine-induced sickness behavior found its own momentum by borrowing from motivational theory. Whether this concept is sufficiently solid to encompass all aspects of the organism's response to stimulation of the innate immune system or must be included in another more basic motivational system, such as the pain defense system, is still disputed.

Figure 3

From cytokine-induced sickness behavior to cytokine-induced depression. Similarities between some of the clinical signs of sickness behavior and some symptoms of depression prompted a series of mechanistic investigations at the experimental level. This took place at a time at which some investigators had already established a data base on immunity and mental health in depressed patients, and they had proposed that some forms of clinical depression could be just another manifestation of an acute phase response. Convergence between these two lines of research provided scientific justification for systematic studies on the effects of exogenously administered cytokines on mood of patients with cancer or subjects with chronic viral infections. This type of approach that investigates relationships between activation of the innate immune system and affective disorders is now being gradually extended to subjects whose innate immune system is chronically activated in pathological (e.g., obesity, coronary heart disease) and physiological (e.g., aging, persons with disabilities) conditions.