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Cited by 1,420Tryptophan and brain disordersNeuroinflammation and Neurodegeneration MechanismsStress Responses and Cortisol

Twenty years of research on cytokine-induced sickness behavior

Open access
Dantzer, Robert, Kelley, Keith W.·2007·Brain, Behavior, and Immunity
DOI 10.1016/j.bbi.2006.09.006PMC PMC1850954
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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.

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  • Pro-inflammatory cytokines resulting from peripheral immunological processes induce sickness behavior with fatigue as a key symptom.

    “a longstanding observation is that pro-inflammatory cytokines, resulting from peripheral (extra-cerebral) immunological processes, induce “sickness behavior” (Dantzer and Kelley, 2007) with fatigue as a key symptom.”

    From Allostatic Self-efficacy: A Metacognitive Theory of Dyshomeostasis-Induced Fatigue and Depression (2016) · cites this paper as Dantzer and Kelley, 2007

  • Sickness is a normal response to infection, characterized by endocrine, autonomic and behavioural changes and triggered by soluble mediators produced at the site of infection by activated accessory immune cells.

    “Sickness is a normal response to infection, just as fear is normal in the face of a predator. It is characterized by endocrine, autonomic and behavioural changes and is triggered by soluble mediators that are produced at the site of infection by activated accessory immune cells.”

    From From inflammation to sickness and depression: when the immune system subjugates the brain (2008) · cites this paper as [1]

  • Acute administration of cytokines or activation of the innate immune system induces sickness behavior including anhedonia, anorexia, fever, sleep changes, and decreased social interaction.

    “Acutely, administration of cytokines or activation of the innate immune system can induce a behavioral repertoire termed “sickness behavior” that includes anhedonia, anorexia, fever, sleep changes, and decreased social interaction (Dunn and Swiergiel, 1998, Dunn et al., 2005, Dantzer and Kelley, 2007).”

    From Inflammatory cytokines in depression: neurobiological mechanisms and therapeutic implications (2013) · cites this paper as Dantzer and Kelley, 2007

  • A microbial challenge that primarily activates the immune system will also prompt neurobehavioral, neuroendocrine, and ANS responses.

    “On the other hand, a microbial challenge that primarily activates the immune system will also prompt neurobehavioral, neuroendocrine, and ANS responses (42, 132).”

    From The Sleep-Immune Crosstalk in Health and Disease (2019) · cites this paper as [132]

  • Sickness behavior represents an element of an adaptive program that has been positively selected for transient immune and inflammatory reactions to limit energy utilization for activities such as foraging and courtship behavior.

    “To explain these seemingly disparate observations, it can be proposed that sickness behavior represents an element of an adaptive program that has been positively selected for transient immune and inflammatory reactions to limit energy utilization for such activities as foraging and courtship behavior [8, 26, 27].”

    From Evolutionary medicine and chronic inflammatory state—known and new concepts in pathophysiology (2012) · cites this paper as [26]

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Authors
Dantzer, R., & Kelley, K. W.
Affiliations
University of Illinois Urbana-Champaign (US)
Corresponding author
Dantzer, Robert
ORCID
Venue
Brain, Behavior, and Immunity
Publisher
Elsevier BV
Published
2007-02
Volume
21
Issue
2
Pages
153-160
ISSN
0889-1591 (ISSN-L)
DOI
10.1016/j.bbi.2006.09.006
PMC
PMC1850954
OpenAlex
W2091975706
Cited by
1,420
References
47
Citations by year
2026: 41 · 2025: 56 · 2024: 77 · 2023: 88 · 2022: 80 · 2021: 92 · 2020: 84 · 2019: 84 · 2018: 77 · 2017: 73 · 2016: 75 · 2015: 99 · 2014: 69 · 2013: 77 · 2012: 78
FWCI
16.30
Type
journal article
Language
en
Open access
Licence
Locations
  • Brain Behavior and Immunity (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Heart, Lung, and Blood Institute (U01HL146201)
  • National Institute of Mental Health (MH 71349, R01MH071349, R01MH051569, MH51569)
  • National Institute of Allergy and Infectious Diseases (R01AI050442, AI50442, U01AI035042)
Topics
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Keywords
sickness behavior, inflammatory cytokines, vagus nerve, innate immunity, depression, Alzheimer's disease, stroke, chronic heart failure, obesity, fatigue, cytokine antagonists, infection recovery
MeSH terms
Adaptation, Physiological, Adaptation, Psychological, Animals, Behavior, Animal, Brain, Humans, Sick Role, Neuroimmunomodulation, Cytokines, Behavioral Research, History, 20th Century, History, 21st Century

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