The role of cytokines in physiological sleep regulation

Ann N Y Acad Sci. 2001 Mar;933:211-21. doi: 10.1111/j.1749-6632.2001.tb05826.x.


Several growth factors (GFs) are implicated in sleep regulation. It is posited that these GFs are produced in response to neural activity and affect input-output relationships within the neural circuits where they are produced, thereby inducing a local state shift. These GFs also influence synaptic efficacy. All the GFs currently identified as sleep regulatory substances are also implicated in synaptic plasticity. Among these substances, the most extensively studied for their role in sleep regulation are interleukin-1beta (IL-1) and tumor necrosis factor alpha (TNF). Injection of IL-1 or TNF enhances non-rapid eye movement sleep (NREMS). Inhibition of either IL-1 or TNF inhibits spontaneous sleep and the sleep rebound that occurs after sleep deprivation. Stimulation of the endogenous production of IL-1 and TNF enhances NREMS. Brain levels of IL-1 and TNF correlate with sleep propensity; for example, after sleep deprivation, their levels increase. IL-1 and TNF are part of a complex biochemical cascade regulating sleep. Downstream events include nitric oxide, growth hormone releasing hormone, nerve growth factor, nuclear factor kappa B, and possibly adenosine and prostaglandins. Endogenous substances moderating the effects of IL-1 and TNF include anti-inflammatory cytokines such as IL-4, IL-10, and IL-13. Clinical conditions altering IL-1 or TNF activity are associated with changes in sleep, for example, infectious disease and sleep apnea. As our knowledge of the biochemical regulation of sleep progresses, our understanding of sleep function and of many clinical conditions will improve.

Publication types

  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Adenosine / physiology
  • Animals
  • Brain / drug effects
  • Brain / physiology
  • Circadian Rhythm
  • Cytokines / physiology*
  • Feedback
  • Gene Expression Regulation
  • Growth Hormone-Releasing Hormone / metabolism
  • Growth Substances / physiology
  • Humans
  • Interleukin-1 / antagonists & inhibitors
  • Interleukin-1 / pharmacology
  • Interleukin-1 / physiology
  • Models, Neurological
  • NF-kappa B / physiology
  • Nerve Growth Factors / physiology
  • Nerve Tissue Proteins / physiology
  • Neuronal Plasticity
  • Nitric Oxide / physiology
  • Receptors, Interleukin-1 / drug effects
  • Receptors, Interleukin-1 / physiology
  • Receptors, Tumor Necrosis Factor / drug effects
  • Receptors, Tumor Necrosis Factor / physiology
  • Sleep / physiology*
  • Sleep Stages / drug effects
  • Sleep Stages / physiology
  • Synapses / physiology
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / pharmacology
  • Tumor Necrosis Factor-alpha / physiology


  • Cytokines
  • Growth Substances
  • Interleukin-1
  • NF-kappa B
  • Nerve Growth Factors
  • Nerve Tissue Proteins
  • Receptors, Interleukin-1
  • Receptors, Tumor Necrosis Factor
  • Tumor Necrosis Factor-alpha
  • Nitric Oxide
  • Growth Hormone-Releasing Hormone
  • Adenosine