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Microbial products and cytokines in sleep and fever regulation
1Department of Physiology and Biophysics, University of Tennessee, Memphis 38163, USA.
Abstract:
Excessive sleepiness and fever are constitutional symptoms associated with systemic infection. Although fevers have been investigated for many years, sleep responses to infectious challenge have only recently been investigated. Inoculation of animals with bacterial, viral, protozoan and fungal organisms result in complex sleep responses dependent upon the microbial agent and route of administration. The general pattern is characterized by an initial robust increase in non-rapid eye movement sleep (NREMS) followed by a period of NREMS inhibition. REMS is inhibited after infectious challenge. The sleep responses are accompanied by fever but the two responses are, in part, independent from each other. Sleep responses, like fevers, may be beneficial to host defense although this area is relatively uninvestigated. Microbial products likely responsible for sleep and fever responses include bacterial muramyl peptides and endotoxin, and viral double stranded RNA. These microbial products induce sleep and fever responses in animal models. The exact mechanism of how these structurally diverse microbial products elicit sleep and fever remain unknown; however these substances share the ability to induce cytokine production. Cytokines such as interleukin-1 (IL-1), tumor necrosis factor, acidic fibroblast growth factor (FGF), and interferon-alpha (IFN-alpha) are somnogenic whether given directly into brain or intravenously. Other cytokines lack somnogenic activity, e.g., IL-2, IL-6, IFN beta and basic FGF. The somnogenic actions of cytokines probably involve growth hormone-releasing hormone (GHRH) and nitric oxide. Anti-GHRH or inhibition of NO production inhibits normal sleep and inhibits IL-1-induced sleep. In conclusion, cytokines are likely key mediators of fever and sleep responses to infection. The microbial-cytokine altered sleep likely results from an amplification of physiological sleep mechanisms which include cytokines, several neuropeptides and neurotransmitters such as nitric oxide.
Insights
Infection triggers complex sleep changes, including increased non-rapid eye movement sleep (NREMS) and inhibited REM sleep, alongside fever. Cytokines are key mediators, potentially enhancing host defense during illness.
Area of Science:
- Immunology
- Neuroscience
- Sleep Medicine
Background:
- Fever and excessive sleepiness are common symptoms of systemic infection.
- While fever has been extensively studied, sleep responses to infection are less understood.
- Infectious agents trigger complex sleep alterations in animal models.
Purpose of the Study:
- To investigate the relationship between infection, fever, and sleep patterns.
- To identify microbial products and endogenous mediators involved in infection-induced sleep changes.
- To explore the potential role of sleep in host defense during infection.
Main Methods:
- Animal models were inoculated with various microbial agents (bacterial, viral, protozoan, fungal).
- Sleep patterns (NREMS, REMS) and body temperature were monitored.
- The effects of microbial products and cytokines on sleep and fever were assessed.
Main Results:
- Infection typically induced an initial increase in NREMS followed by inhibition, and REMS inhibition.
- Sleep responses occurred alongside fever, but were partially independent.
- Microbial products like muramyl peptides and double-stranded RNA induced sleep and fever.
- Cytokines, including IL-1 and TNF, were identified as somnogenic mediators.
Conclusions:
- Cytokines are likely central mediators of both fever and sleep responses to infection.
- Infection-induced sleep alterations may involve amplified physiological sleep mechanisms.
- Sleep, like fever, might play a beneficial role in host defense during infection.