How Cytokines Regulate Sleep

Cytokines are best known for their role as the immune system’s mediators. However, according to accumulating research, they also have a vital role in sleep regulation or sleep-wake homeostasis.

Although decades are passing by and we’re continually finding new, exciting angles to study sleep, the unexplored area doesn’t seem to get any smaller. If anything, with how much progress we’ve made by now, it seems we’re only beginning to understand how tangled and complex our brains are, and not just when it comes to sleep.

The realization of how much we don’t know is humbling, but it also sparks a great deal of curiosity as to what we’ve yet to learn. The amount of knowledge we’ve accumulated by now makes us that much faster and more efficient in finding out new information. A lot of ground has been set, but even so, loose ends can be found in almost any corner of current research. To make it a more understandable and accessible point of reference to build on later, researchers have proposed different models and theories explaining what goes on inside our brains during sleep.

The two-process model of sleep regulation is globally accepted as the most authoritative posit today. We will take a closer look at it further down in this article, but for now, let’s say it’s a well-done sketch rather than the entire painting. Though this model provides a good angle to observe the core processes of sleep, its overly black-and-white, basic nature fails to demonstrate how inseparable and interconnected these processes are, as well as the many other factors that come into play besides them. It is partly intentional, to make it more widely accessible, and partly due to our lack of complete information necessary to form such a precise overview. In any case, it’s essential to note that all bodily processes, and not just those closely related to sleep regulation, have an impact on our well-being and sleep. After all, the quality of our sleep directly affects other aspects of our health, so it isn’t strange that the transaction can go in the opposite direction, too. One key element of our health and a cog in the sleep mechanism is our immune system.

Immune System

Our immune system is the main line of defense against bacteria, viruses, and infections. It is a network made of cells and tissues assigned with different tasks to ensure we’re able to maintain our health. When we feel worn out, weak, or get sick, that means our body’s under siege, and our immune system is taking up most of our energy to fight off the intruders. Too many blows and our immunity can be weakened, lowering its ability to protect us and resulting in the same cold or sickness returning a couple of times after it seemed to be gone.

The immune system is comprised of barriers that intercept any form of a pathogen in their way. It is tightly intertwined with other systems in our body, like the endocrine, and nervous system, and has a crucial role in our ability to regenerate other cells. When coming in contact with pathogens, our body needs to recognize their type to be able to call for appropriate action. This is the so-called “adaptive immunity” trying to be very specific and effective in how we will respond to the threat, and saving us the trouble of going all-out every time we get a cold. Adaptive immunity is the more serious and narrowly targeted mechanism, contrasting to the standard procedure of our “innate” immune system – the default setting of our bodies, doing patrols and sending generic responses when certain alarms go off. The main types of cells to keep in mind here are called T-cells and B-cells.

Their distinction is quite simple and shows the moment they run into a pathogen. In order to recognize that a cell is, in fact, foreign, both T-cells and B-cells carry small screening receptors. For a T-cell, this is not enough; it needs an additional, “self” molecule (called MHC) to serve as sort of a mirror and make it evident that a pathogen looks differently. B-cells, however, don’t require such assistance as it carries an antibody on its surface. Subgroups exist of both of these cell types; a complete set of B-cells represents all the antibodies our organisms can produce. Furthermore, the adaptive mechanism is the one that can remember infections and bacteria once they have been successfully dealt with. This feature is a significant point of our evolutionary progress and a crucial factor in our ability to overcome and avoid future diseases.

Besides the T- and B-cells and their variants, other elements like some hormones, proteins, and vitamins have a role in how, when, and how well our body will defend itself against invasions. It’s also important to note that our immunity, like all other systems in our bodies, can work against us instead of protecting us. This happens when our healthy, normal cells get targeted and damaged by the diseased immune system that stops differentiating between friends and foes in our organisms.

The Link Between the Immune System and Sleep

We’ve just scratched the surface. By now, you should understand a couple of things:

  • There are two different categories of the immune system, the innate and the adaptive one
  • The innate one is the autopilot; it recognizes patterns and sends generic responses
  • The adaptive system is the manual option; it seeks out various types of pathogens and responds on a more personal level. It also learns and remembers stress it’s overcome and keeps the antibodies so that the diseases can’t repeat.
  • Antibodies aren’t the only thing in our arsenal against infections.
  • A disordered immune system can become diseased, and mistakenly start working against us.


But let’s zoom out for a second. What does all of this mean in terms of everyday life? What makes our defenses impeccable or meek and easy to breach?

There are some ordinary things we consider significant when it comes to our health, and some measures we take to liven up when we get sick. For the majority of people, vitamin supplements, leafy-green diets, and exercise take the first few spots on the list when they feel good, while soups and rest come up only when we are already under the weather. This about sums up the problem: we are willing to try any shortcut to boost our health, but getting to a point when we’ll consider prioritizing sleep usually requires failed quick alternatives, and sometimes weeks of therapy. As a consequence, up to 20% of adults cut their sleep short by 90 minutes on average, and many frequently experience excessive daytime sleepiness. Others have it worse, where insufficient sleep leads to sleep deprivation, marking about half way to forming a sleep disorder.

But, apart from sleep deprivation further impairing your sleep, it also takes a toll on other areas of your health. One of them, you guessed it, is your immune system.

Due to its regenerative and protective role, it’s hardly surprising that lack of sleep can mess up your busy schedule. When your sleep quality or duration goes down, they bring everything down with them. Say you had a busy week at work and had to pull a couple of allnighters to tie all loose ends. The lack of sleep and the stress you went through at the same time don’t just add up; they get magnified. Sleep deprivation impairs your cognitive abilities and emotional well-being, making you perform worse than usual at work. Difficult as it is to make your deadline, you also feel miserable, and on top of that, you stress because you realize all of this and feel its weight. Now, the lack of sleep made sure your defenses are lowered, and your body isn’t regenerating as quickly as it usually is. The amount of stress you are experiencing builds onto this, and before you know it, you’re sick.

In a brighter scenario, sufficient amount and quality of sleep promote a healthy immune system and strengthen it, fighting off any traces of inflammation quickly and effectively. In the other way around, your immunity also has a role in sleep regulation. It is clearly shown in the way your sleep structure changes when you’re ill, but there’s more to it than that. In order to better understand the immune system and sleep, there’s another essential factor we need to introduce to the story – cytokines.

What are Cytokines?

These small proteins are the immune system’s mediators that have a significant role in cell activity and communication. Depending on which type of cell releases them and how they work, they can be categorized as lymphokines, monokines, chemokines, and interleukin (IL), although researchers recently concluded that these categories aren’t strict due to the redundancy of most cytokines. 

As there are cytokines that don’t display redundancy, they are listed into structural categories:

  • The four-α-helix bundle family, with subfamilies IL-2, Interferon (IFN), and IL-10.
  • The IL-1 family
  • The IL-17 family
  • The cysteine-knot cytokines

More importantly, cytokine action can also be classified into three groups based on which type of cell they tend to:

  • Autocrine action focuses on the cells that made the cytokines
  • Paracrine action focuses on nearby cells
  • Endocrine action focuses on cells that are further away

A group of cells often creates a single cytokine for a specific task. When acting on cells, cytokines stimulate them to generate more cytokines.

These proteins can sometimes be confused with hormones. The exact distinction isn’t completely known yet, but there are some pointers in this direction. For one, the range of hormone magnitudes is very narrow, while cytokine concentration may start out smaller but gets increased up to 1000 times during an infection or similar stressful event. Moreover, these proteins can be produced by almost any cell that has a nucleus, and anywhere in the body, while hormones are secreted by specific glands. Lastly, the role of cytokines doesn’t end at one’s immune system. These proteins are involved in initiating pathological pain and its duration, inflammation-induced nerve sensitization, but also, according to accumulating research, sleep.

Cytokines and Sleep

There are some basic criteria that peptides and other substances need to pass to qualify as Sleep Regulatory Substances (SRS) according to the PMC. Here are some of them:

SRS needs to enhance the duration of a sleep stage or the EEG wave power

Reduced SRS has to reduce spontaneous sleep

The amount of SRS in the brain needs to be linked with sleep propensity.

Cytokines fulfill all of these criteria and more, proving their connection with sleep-related processes in our bodies. IL-1 and TNF (tumor necrosis factor), in particular, have been widely accepted as two essential contributors to the sleep-wake homeostasis. This process, along with the circadian rhythm, is a key point in the two-process model of sleep regulation. Homeostatic processes throughout your body are in charge of micromanaging different systems, including temperature regulation, insulin levels, etc. As each homeostasis has its own subject, the sleep-wake homeostasis (or process S) is what makes you increasingly sleepy as the day goes by and builds the pressure to indicate you need rest.

In contrast to process S, the circadian rhythm (also known as process C) works as your internal clock, in tune with the external time of the day. Basically, by recognizing clues such as light, your circadian rhythm has a good idea when it’s daytime or nighttime outside and aims to synchronize your sleep accordingly. That means it will keep you alert during most of the day, but open the gates when the night falls for sleep-inducing processes and secretion of hormones like melatonin.

In the mechanism of these two processes and their correlation, IL-1 and TNF have sort of a bridge function. If either of these cytokines gets inhibited, it shows, as your sleep gets disrupted either in the middle of the night (IL-1) or just before dawn (TNF). These two also interfere with the expression of some clock genes, which have a part in the circadian rhythm.

Moreover, both IL-1 and TNF influence and increase the duration of NREM sleep, as well as the EEG power in humans and many other species. The more of these SRSs you have in your body, the longer time you will spend in NREM, especially slow wave sleep. It also means that these proteins are elevated during many health conditions you may experience – chronic fatigue, insomnia, sleep apnea, AIDS, alcoholism, Alzheimer’s disease, and many more. All of these are linked with insufficient sleep, excessive daytime sleepiness, and often, a weak immune system.

IL-1 levels also peak at the moment before you fall asleep and are heightened when you’re sleep deprived. It signifies a correlation with the sleep-wake homeostasis, which is also at its all-time high during sleep onset and then gradually lowers right until you wake up.

Other cytokines are also being studied because of their connection to sleep. They include IL-2, IL-6, IL-8, IL-15, and IL-18. Some others potentially affect NREM, too, but it is too soon to tell how exactly they work. Lastly, some neutrophils also can induce NREM and REM sleep.

Unanswered Questions for Further Research

The relationship of all cells in our organisms are complex, and almost certainly impossible for us to fully understand at this point. It is especially interesting to learn about the substances that are meant to connect and affect other cells and systems and study all the ways they are useful (and sometimes harmful) to our health. A lot of research is currently taking place in hopes to clarify the role of cytokines as sleep regulatory substances further, but also unrelated to sleep. Many studies and hypothesis’ have yet to be attempted, and the existing ones approved. However, some ground has been set, and researchers have strong reasons to believe they will discover a whole lot more when it comes to this topic. Here are some points that are being considered and tested as we speak, and some that may spark further research:

  • The role of cytokines in cortical column state
  • The neuroconnective feature of sleep and its link to cytokines
  • The Adenosine Triphosphate-Cytokine-Adenosine Hypothesis
  • The role of cytokines in physiological sleep regulation


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