Named Series: Twenty Years of Brain Behavior and Immunity
Twenty years of research on cytokine-induced sickness behavior

https://doi.org/10.1016/j.bbi.2006.09.006Get rights and content

Abstract

Cytokine-induced sickness behavior was recognized within a few years of the cloning and expression of interferon-α, 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.

Introduction

The first paper on sickness behavior was published in Brain, Behavior, and Immunity (BBI) by Aubert et al. (1995). Since then, 39 papers on sickness behavior have been published in the journal, which represent 20 percent of the 192 papers published on cytokine-induced sickness behavior that are listed in PubMed. Despite some risk of overlap, it would be fair to add to these statistics the 14 papers on cytokines and depression that were published in BBI in 2002. Although the familiar phrase that “statistics lie and statistician’s use statistics” is apropos in the sense that statistics can be used to describe nearly anything one wants them to tell, it is clear from this cursory quantitative review of the literature that BBI has been instrumental in promoting the concept of cytokine-induced sickness behavior. This conclusion becomes even more obvious when these figures are compared to the 52 papers on cytokines and the brain that were published by BBI and contrast with the 15,382 papers listed by PubMed in this field (as of July 27, 2006). BBI has not been the home journal of those scientists who study the expression and actions of cytokines in the brain. Its niche is clearly at the interface between immunity and behavior in physiological and pathological conditions. The objective of this article is not to add another paper on cytokine-induced sickness behavior to the list of those already published by BBI but to show why it was and remains logical for BBI to play an instrumental role in the publication of the results on cytokine-induced sickness behavior.

Section snippets

Before 1987: The history of sickness behavior

The study of sickness has a rich history in psychology and behavioral pharmacology (Fig. 1). In psychology, research on the concept of sickness started in the mid-fifties with Garcia’s work on bait shyness (Garcia et al., 1955). Garcia explained the fact that rodents cannot be poisoned very easily by their propensity to develop learned aversions to the new taste of any compound that induces gastro-intestinal malaise. At the time this research was carried out, the laws of learning were dominated

From 1987 to 1996: The merging of sickness behavior with immunology

The way the concept of sickness behavior merged with immunology is summarized in Fig. 2. Prior to 1987, the biological activities of “endogenous pyrogen,” “leukocyte endogenous mediator,” and “lymphocyte activating factor” were suspected to be derived from a single protein. That protein was eventually purified, renamed as IL-1, and was shown to be active in the brain, as determined by induction of both fever in rabbits and EEG signals associated with slow-wave sleep in rats. However, the very

From 1997 to 2006: The move from sickness to depression

The way the concept of cytokine-induced sickness behavior merged with the field of mental health is illustrated in Fig. 3. Defining cytokine-induced sickness behavior as a motivational state implies that it belongs in the realm of physiology, just as fear, hunger, thirst and other motivational states. To be able to withdraw from the environment, seek rest and care for the body is as normal in response to infectious agents as being able to shift to a state of increased arousal and readiness for

2007 and beyond: The move to translational research

Cytokine-induced sickness behavior is no longer a curiosity. In animal research, its measurement has become a standard procedure for assessing the mode of functioning of communication pathways from the immune system to the brain as well as the sensitivity of the brain to direct immune stimulation. At the clinical level, many investigators are now actively engaged in collecting the type of evidence that is necessary to test the possibility that many of the subjective complaints of patients

Acknowledgment

This work was supported by the NIH to K.W.K. (MH51569 and AI50442) and R.D. (MH71349).

References (44)

  • R. Dantzer et al.

    Stress and immunity: an integrated view of relationships between the brain and the immune system

    Life Sci.

    (1989)
  • B.L. Hart

    Biological basis of the behavior of sick animals

    Neurosci. Biobehav. Rev.

    (1988)
  • S. Kent et al.

    Effects of lipopolysaccharide on food-motivated behavior in the rat are not blocked by an interleukin-1 receptor antagonist

    Neurosci. Lett.

    (1992)
  • J.P. Konsman et al.

    Cytokine-induced sickness behaviour: mechanisms and implications

    Trends Neurosci.

    (2002)
  • M. Maes et al.

    The monocyte–T-lymphocyte hypothesis of major depression

    Psychoneuroendocrinology

    (1995)
  • S.F. Maier et al.

    Interleukin-1 mediates the behavioral hyperalgesia produced by lithium chloride and endotoxin

    Brain Res.

    (1993)
  • J.J. McGlone et al.

    The antiaggressive effect of lithium is abolished by area postrema lesion

    Physiol. Behav.

    (1980)
  • S. Ritter et al.

    Absence of lithium-induced taste aversion after area postrema lesion

    Brain Res.

    (1980)
  • A. Tazi et al.

    Interleukin-1 induces conditioned taste aversion in rats: a possible explanation for its pituitary–adrenal stimulating activity

    Brain Res.

    (1988)
  • P.E. Auron et al.

    Nucleotide sequence of human monocyte interleukin 1 precursor cDNA

    Proc. Natl. Acad. Sci. USA

    (1984)
  • F. Berkenbosch et al.

    Corticotropin-releasing factor-producing neurons in the rat activated by interleukin-1

    Science

    (1987)
  • H. Besedovsky et al.

    Immunoregulatory feedback between interleukin-1 and glucocorticoid hormones

    Science

    (1986)
  • Cited by (0)

    View full text