Dose-dependent effects of endotoxin on human sleep
Abstract
The role of the central nervous system in the host response to infection and inflammation and modulation of these responses by the hypothalamic-pituitary-adrenal system are well established. In animals, activation of host defense mechanisms increases non-rapid eye movement (NREM) sleep amount and intensity, which, in turn, are thought to support host defense, or the body's ability to defend itself against challenges to its immune system. In humans, the evidence is conflicting. Therefore, we investigated the effects of three placebo-controlled doses of endotoxin on host response, including nocturnal sleep in healthy volunteers. Administered before nocturnal sleep onset, endotoxin dose dependently increased rectal temperature, heart rate, and the plasma levels of tumor necrosis factor (TNF)-α, soluble TNF receptors, interleukin (IL)-1 receptor antagonist, IL-6, and cortisol. The lowest dose reliably increased circulating levels of cytokines and soluble cytokine receptors, but it did not affect rectal temperature, heart rate, or cortisol. This subtle host defense activation increased deep NREM sleep amount, often referred to as slow-wave sleep (stages 3 and 4), and intensity (delta power). Conversely, the highest dose of endotoxin disrupted sleep. Whereas it is well established that the endocrine and thermoregulatory systems are very sensitive to endotoxin, this study shows that human sleep-wake behavior is even more sensitive to activation of host defense mechanisms.
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More robust immune activation decreased NREM sleep.
“Specifically, low-level immune activation leads to increased non-rapid eye movement (NREM) sleep, while decreasing or having no effect on REM sleep; in contrast, more robust immune activation decreased both NREM and REM sleep (Mullington et al., 2000).”
From The role of inflammation in core features of depression: Insights from paradigms using exogenously-induced inflammation. (2018) · cites this paper as Mullington et al., 2000
Low-level immune activation leads to increased non-rapid eye movement (NREM) sleep.
“Specifically, low-level immune activation leads to increased non-rapid eye movement (NREM) sleep, while decreasing or having no effect on REM sleep; in contrast, more robust immune activation decreased both NREM and REM sleep (Mullington et al., 2000).”
From The role of inflammation in core features of depression: Insights from paradigms using exogenously-induced inflammation. (2018) · cites this paper as Mullington et al., 2000
More robust immune activation decreased REM sleep.
“Specifically, low-level immune activation leads to increased non-rapid eye movement (NREM) sleep, while decreasing or having no effect on REM sleep; in contrast, more robust immune activation decreased both NREM and REM sleep (Mullington et al., 2000).”
From The role of inflammation in core features of depression: Insights from paradigms using exogenously-induced inflammation. (2018) · cites this paper as Mullington et al., 2000
Moderate doses of endotoxin (0.8 ng/kg) reduced total sleep time.
“For example, very low doses of endotoxin (0.2 ng/kg) promoted sleep, whereas moderate doses (0.8 ng/kg) reduced total sleep time and increased sleep onset latency (Hermann et al., 1998; Korth et al., 1996; Mullington et al., 2000).”
From The role of inflammation in core features of depression: Insights from paradigms using exogenously-induced inflammation. (2018) · cites this paper as Mullington et al., 2000
Very low doses of endotoxin (0.2 ng/kg) promoted sleep.
“For example, very low doses of endotoxin (0.2 ng/kg) promoted sleep, whereas moderate doses (0.8 ng/kg) reduced total sleep time and increased sleep onset latency (Hermann et al., 1998; Korth et al., 1996; Mullington et al., 2000).”
From The role of inflammation in core features of depression: Insights from paradigms using exogenously-induced inflammation. (2018) · cites this paper as Mullington et al., 2000
Low-level immune activation decreases or has no effect on REM sleep.
“Specifically, low-level immune activation leads to increased non-rapid eye movement (NREM) sleep, while decreasing or having no effect on REM sleep; in contrast, more robust immune activation decreased both NREM and REM sleep (Mullington et al., 2000).”
From The role of inflammation in core features of depression: Insights from paradigms using exogenously-induced inflammation. (2018) · cites this paper as Mullington et al., 2000
Moderate doses of endotoxin (0.8 ng/kg) increased sleep onset latency.
“For example, very low doses of endotoxin (0.2 ng/kg) promoted sleep, whereas moderate doses (0.8 ng/kg) reduced total sleep time and increased sleep onset latency (Hermann et al., 1998; Korth et al., 1996; Mullington et al., 2000).”
From The role of inflammation in core features of depression: Insights from paradigms using exogenously-induced inflammation. (2018) · cites this paper as Mullington et al., 2000
Exogenously-induced inflammation using both endotoxin and IFN-α also led to a suppression of REM sleep.
“However, exogenously-induced inflammation using both endotoxin and IFN-α also led to a suppression of REM sleep (Mullington et al., 2000; Raison et al., 2010), which is the opposite of changes observed in depressed patients (Palagini et al., 2013; Riemann et al., 2001; Tsuno et al., 2005).”
From The role of inflammation in core features of depression: Insights from paradigms using exogenously-induced inflammation. (2018) · cites this paper as Mullington et al., 2000
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 [5]
LPS is involved in sleep responses to gram-negative bacteria and has been studied in animal models and human volunteers.
“Another bacterial product that is involved in sleep responses to gram-negative bacteria is the LPS component of cell wall endotoxin.LPS and has been intensively studied in animal models and humans volunteers with respect to effects on sleep”
From Sleep health: Reciprocal regulation of sleep and innate immunity (2017) · cites this paper as Mullington et al, 2000
Healthy human volunteers injected with LPS manifest sleep changes, fever, cytokine expression, and hormonal changes somewhat similar to those seen in animals.
“Healthy human volunteers injected with LPS manifest sleep changes, fever, cytokine expression, and hormonal changes (Mullington and Korth et al, 2000) somewhat similar to those seen in animals.”
From Sleep health: Reciprocal regulation of sleep and innate immunity (2017) · cites this paper as Mullington and Korth et al, 2000
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References 46 · Cited by 226
- Authors
- Mullington, J., Korth, C., Hermann, D. M., Orth, A., Galanos, C., Holsboer, F., & Pollmächer, T.
- Affiliations
- Max Planck Institute of Psychiatry (DE)
- Venue
- American Journal of Physiology-Regulatory, Integrative and Comparative Physiology
- Publisher
- American Physiological Society
- Published
- 2000-04-01
- Volume
- 278
- Issue
- 4
- Pages
- R947-R955
- ISSN
- 0363-6119 (ISSN-L)
- 1522-1490
- OpenAlex
- W1880976932
- Cited by
- 226
- References
- 46
- Citations by year
- 2026: 3 · 2025: 9 · 2024: 9 · 2023: 7 · 2022: 7 · 2021: 7 · 2020: 9 · 2019: 12 · 2018: 9 · 2017: 7 · 2016: 9 · 2015: 14 · 2014: 7 · 2013: 10 · 2012: 12
- FWCI
- 5.65
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Regulatory, Integrative and Comparative Physiology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Medicine › Critical Care and Intensive Care Medicine › Thermal Regulation in Medicine
- Keywords
- endotoxin, sleep, slow-wave sleep, NREM sleep, host defense, inflammation, cytokines, TNF-α, interleukin-6, interleukin-1 receptor antagonist, soluble TNF receptors, cortisol, hypothalamic-pituitary-adrenal axis, dose-dependent effects, sleep disruption, thermoregulation, heart rate
- MeSH terms
- Adult, Body Temperature Regulation, Dose-Response Relationship, Drug, Electroencephalography, Electromyography, Electrooculography, Fever, Heart Rate, Humans, Hydrocortisone, Hypothalamo-Hypophyseal System, Injections, Intravenous, Leukocyte Count, Lipopolysaccharides, Male, Pituitary-Adrenal System, Sialoglycoproteins, Sleep Stages, Tumor Necrosis Factor-alpha, Neuroimmunomodulation, Interleukin-6, Single-Blind Method, Interleukin 1 Receptor Antagonist Protein
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