Cytokine-induced sickness behavior: where do we stand?
Abstract
Sickness behavior refers to the coordinated set of behavioral changes that develop in sick individuals during the course of an infection. At the molecular level, these changes are due to the effects of proinflammatory cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNFalpha), in the brain. Peripherally released cytokines act on the brain via a fast transmission pathway involving primary afferent nerves innervating the body site of inflammation and a slow transmission pathway involving cytokines originating from the choroid plexus and circumventricular organs and diffusing into the brain parenchyma by volume transmission. At the behavioral level, sickness behavior appears to be the expression of a central motivational state that reorganizes the organism's priorities to cope with infectious pathogens. There is clinical and experimental evidence that activation of the brain cytokine system is associated with depression, although the exact relationship between sickness behavior and depression is still elusive.
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Peripherally produced pro-inflammatory cytokines act on the brain to cause the behavioural symptoms of sickness.
“However, these peripherally produced cytokines also act on the brain to cause the aforementioned behavioural symptoms of sickness.”
From From inflammation to sickness and depression: when the immune system subjugates the brain (2008) · cites this paper as [4]
Sickness behaviour is an expression of a previously unrecognized motivational state responsible for reorganizing perceptions and actions to enable ill individuals to cope better with an infection.
“Recently, it has been suggested that ‘sickness behaviour’2,3, a term used to describe the drastic changes in subjective experience and behaviour that occur in physically ill patients and animals, is an expression of a previously unrecognized motivational state. It is responsible for re-organizing perceptions and actions to enable ill individuals to cope better with an infection4.”
From From inflammation to sickness and depression: when the immune system subjugates the brain (2008) · cites this paper as [4]
IL-6 administered systemically or centrally has no behavioural effect despite its ability to induce a fever response.
“In contrast to IL-1β and TNF-α, IL-6 administered systemically or centrally has no behavioural effect despite its ability to induce a fever response4.”
From From inflammation to sickness and depression: when the immune system subjugates the brain (2008) · cites this paper as [4]
Systemic or central administration of IL-1β or TNF-α to rats and mice induces the full spectrum of behavioural signs of sickness in a dose- and time-dependent manner.
“Pharmacological experiments have amply demonstrated that systemic or central administration of IL-1β or TNF-α to rats and mice induces the full spectrum of behavioural signs of sickness in a dose- and time-dependent manner4.”
From From inflammation to sickness and depression: when the immune system subjugates the brain (2008) · cites this paper as [4]
In response to a peripheral infection, innate immune cells produce pro-inflammatory cytokines that act on the brain to cause sickness behaviour.
“In response to a peripheral infection, innate immune cells produce pro-inflammatory cytokines that act on the brain to cause sickness behaviour.”
From From inflammation to sickness and depression: when the immune system subjugates the brain (2008) · cites this paper as [4]
The main pro-inflammatory cytokines involved in sickness behaviour are IL-1β and TNF-α.
“The main pro-inflammatory cytokines involved in sickness behaviour are IL-1β and TNF-α.”
From From inflammation to sickness and depression: when the immune system subjugates the brain (2008) · cites this paper as [4]
Behavioral changes induced by immune activation include psychomotor slowing, social withdrawal, anhedonia, depressed mood, and disturbed sleep architecture, collectively termed sickness behavior.
“Behavioral changes induced by immune activation include symptoms such as psychomotor slowing, social withdrawal, anhedonia, depressed mood, and disturbed sleep architecture, collectively termed “sickness behavior” [4], [5], [6].”
From Dose-dependent effects of endotoxin on neurobehavioral functions in humans (2011) · cites this paper as [4]
The discrepancy underlines the basic independency of these two processes and might fortify the view on sickness behavior as an adaptive response rather than a simple impairment by the inflammatory challenge.
“Although the reasons for this discrepancy remain unclear, it underlines the basic independency of these two processes and might fortify the view on sickness behavior as an adaptive response rather than a simple impairment by the inflammatory challenge [4].”
From Dose-dependent effects of endotoxin on neurobehavioral functions in humans (2011) · cites this paper as [4]
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- Authors
- Dantzer, R.
- Affiliations
- Inserm (FR)
- Corresponding author
- Dantzer, Robert
- ORCID
- Dantzer, Robert
- Venue
- Brain, Behavior, and Immunity
- Publisher
- Elsevier BV
- Published
- 2001-03
- Volume
- 15
- Issue
- 1
- Pages
- 7-24
- ISSN
- 0889-1591 (ISSN-L)
- OpenAlex
- W2035121795
- Cited by
- 862
- References
- 62
- Citations by year
- 2026: 11 · 2025: 34 · 2024: 30 · 2023: 23 · 2022: 28 · 2021: 36 · 2020: 55 · 2019: 35 · 2018: 35 · 2017: 33 · 2016: 29 · 2015: 42 · 2014: 35 · 2013: 34 · 2012: 38
- FWCI
- 14.25
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Brain Behavior and Immunity (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- Vedecká Grantová Agentúra MŠVVaŠ SR a SAV
- National Institutes of Health (5r01dk049311-05)
- National Institute of Mental Health (R01MH051569, MH51569-02)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 49311)
- 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, interleukin-1, TNF-α, choroid plexus, circumventricular organs, volume transmission, depression, infection
- MeSH terms
- Brain, Humans, Psychoneuroimmunology, Sick Role, Neuroimmunomodulation, Cytokines
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