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Cortisol and inflammation

Cortisol and inflammation


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Cortisol is released under stressful condition. It is known to have anti-inflammatory role. In fact it is used as potent anti-inflammatory drug also.

Though stressful conditions are unwanted and unfavorable, the body's response to such conditions by releasing cortisol, seems to be beneficial only.

If so, why cortisol is considered as undesirable and dangerous?


How stress influences disease: Study reveals inflammation as the culprit

Stress wreaks havoc on the mind and body. For example, psychological stress is associated with greater risk for depression, heart disease and infectious diseases. But, until now, it has not been clear exactly how stress influences disease and health.

A research team led by Carnegie Mellon University's Sheldon Cohen has found that chronic psychological stress is associated with the body losing its ability to regulate the inflammatory response. Published in the Proceedings of the National Academy of Sciences, the research shows for the first time that the effects of psychological stress on the body's ability to regulate inflammation can promote the development and progression of disease.

"Inflammation is partly regulated by the hormone cortisol and when cortisol is not allowed to serve this function, inflammation can get out of control," said Cohen, the Robert E. Doherty Professor of Psychology within CMU's Dietrich College of Humanities and Social Sciences.

Cohen argued that prolonged stress alters the effectiveness of cortisol to regulate the inflammatory response because it decreases tissue sensitivity to the hormone. Specifically, immune cells become insensitive to cortisol's regulatory effect. In turn, runaway inflammation is thought to promote the development and progression of many diseases.

Cohen, whose groundbreaking early work showed that people suffering from psychological stress are more susceptible to developing common colds, used the common cold as the model for testing his theory. With the common cold, symptoms are not caused by the virus -- they are instead a "side effect" of the inflammatory response that is triggered as part of the body's effort to fight infection. The greater the body's inflammatory response to the virus, the greater is the likelihood of experiencing the symptoms of a cold.

In Cohen's first study, after completing an intensive stress interview, 276 healthy adults were exposed to a virus that causes the common cold and monitored in quarantine for five days for signs of infection and illness. Here, Cohen found that experiencing a prolonged stressful event was associated with the inability of immune cells to respond to hormonal signals that normally regulate inflammation. In turn, those with the inability to regulate the inflammatory response were more likely to develop colds when exposed to the virus.

In the second study, 79 healthy participants were assessed for their ability to regulate the inflammatory response and then exposed to a cold virus and monitored for the production of pro-inflammatory cytokines, the chemical messengers that trigger inflammation. He found that those who were less able to regulate the inflammatory response as assessed before being exposed to the virus produced more of these inflammation-inducing chemical messengers when they were infected.

"The immune system's ability to regulate inflammation predicts who will develop a cold, but more importantly it provides an explanation of how stress can promote disease," Cohen said. "When under stress, cells of the immune system are unable to respond to hormonal control, and consequently, produce levels of inflammation that promote disease. Because inflammation plays a role in many diseases such as cardiovascular, asthma and autoimmune disorders, this model suggests why stress impacts them as well."

He added, "Knowing this is important for identifying which diseases may be influenced by stress and for preventing disease in chronically stressed people."

In addition to Cohen, the research team included CMU's Denise Janicki-Deverts, research psychologist Children's Hospital of Pittsburgh's William J. Doyle University of British Columbia's Gregory E. Miller University of Pittsburgh School of Medicine's Bruce S. Rabin and Ellen Frank and the University of Virginia Health Sciences Center's Ronald B. Turner.

The National Center for Complementary and Alternative Medicine, National Institute of Mental Health, National Heart, Lung and Blood Institute and the MacArthur Foundation Research Network on Socioeconomic Status and Health funded this research.


Cortisol and inflammation - Biology

November 2009 Issue

Cortisol — Its Role in Stress, Inflammation, and Indications for Diet Therapy
By Dina Aronson, MS, RD
Today’s Dietitian
Vol. 11 No. 11 P. 38

Cortisol, a glucocorticoid (steroid hormone), is produced from cholesterol in the two adrenal glands located on top of each kidney. It is normally released in response to events and circumstances such as waking up in the morning, exercising, and acute stress. Cortisol’s far-reaching, systemic effects play many roles in the body’s effort to carry out its processes and maintain homeostasis.

Of interest to the dietetics community, cortisol also plays an important role in human nutrition. It regulates energy by selecting the right type and amount of substrate (carbohydrate, fat, or protein) the body needs to meet the physiological demands placed on it. When chronically elevated, cortisol can have deleterious effects on weight, immune function, and chronic disease risk.

Cortisol (along with its partner epinephrine) is best known for its involvement in the “fight-or-flight” response and temporary increase in energy production, at the expense of processes that are not required for immediate survival. The resulting biochemical and hormonal imbalances (ideally) resolve due to a hormonally driven negative feedback loop. The following is a typical example of how the stress response operates as its intended survival mechanism:

1. An individual is faced with a stressor.

2. A complex hormonal cascade ensues, and the adrenals secrete cortisol.

3. Cortisol prepares the body for a fight-or-flight response by flooding it with glucose, supplying an immediate energy source to large muscles.

4. Cortisol inhibits insulin production in an attempt to prevent glucose from being stored, favoring its immediate use.

5. Cortisol narrows the arteries while the epinephrine increases heart rate, both of which force blood to pump harder and faster.

6. The individual addresses and resolves the situation.

7. Hormone levels return to normal.

So what’s the problem? In short, the theory is that with our ever-stressed, fast-paced lifestyle, our bodies are pumping out cortisol almost constantly, which can wreak havoc on our health. This whole-body process, mediated by hormones and the immune system, identifies cortisol as one of the many players. But isolating its role helps put into context the many complex mechanisms that lead to specific physiological damage.

Whole-Body Effects of Elevated Cortisol

Blood Sugar Imbalance and Diabetes
Under stressful conditions, cortisol provides the body with glucose by tapping into protein stores via gluconeogenesis in the liver. This energy can help an individual fight or flee a stressor. However, elevated cortisol over the long term consistently produces glucose, leading to increased blood sugar levels.

Theoretically, this mechanism can increase the risk for type 2 diabetes, although a causative factor is unknown.1 Since a principal function of cortisol is to thwart the effect of insulin—essentially rendering the cells insulin resistant—the body remains in a general insulin-resistant state when cortisol levels are chronically elevated. Over time, the pancreas struggles to keep up with the high demand for insulin, glucose levels in the blood remain high, the cells cannot get the sugar they need, and the cycle continues.

Weight Gain and Obesity
Repeated elevation of cortisol can lead to weight gain.2 One way is via visceral fat storage. Cortisol can mobilize triglycerides from storage and relocate them to visceral fat cells (those under the muscle, deep in the abdomen). Cortisol also aids adipocytes’ development into mature fat cells. The biochemical process at the cellular level has to do with enzyme control (11-hydroxysteroid dehydrogenase), which converts cortisone to cortisol in adipose tissue. More of these enzymes in the visceral fat cells may mean greater amounts of cortisol produced at the tissue level, adding insult to injury (since the adrenals are already pumping out cortisol). Also, visceral fat cells have more cortisol receptors than subcutaneous fat.

A second way in which cortisol may be involved in weight gain goes back to the blood sugar-insulin problem. Consistently high blood glucose levels along with insulin suppression lead to cells that are starved of glucose. But those cells are crying out for energy, and one way to regulate is to send hunger signals to the brain. This can lead to overeating. And, of course, unused glucose is eventually stored as body fat.

Another connection is cortisol’s effect on appetite and cravings for high-calorie foods. Studies have demonstrated a direct association between cortisol levels and calorie intake in populations of women.3 Cortisol may directly influence appetite and cravings by binding to hypothalamus receptors in the brain. Cortisol also indirectly influences appetite by modulating other hormones and stress responsive factors known to stimulate appetite.

Immune System Suppression
Cortisol functions to reduce inflammation in the body, which is good, but over time, these efforts to reduce inflammation also suppress the immune system. Chronic inflammation, caused by lifestyle factors such as poor diet and stress, helps to keep cortisol levels soaring, wreaking havoc on the immune system. An unchecked immune system responding to unabated inflammation can lead to myriad problems: an increased susceptibility to colds and other illnesses, an increased risk of cancer, the tendency to develop food allergies, an increased risk of an assortment of gastrointestinal issues (because a healthy intestine is dependent on a healthy immune system), and possibly an increased risk of autoimmune disease.4,5

Gastrointestinal Problems
Cortisol activates the sympathetic nervous system, causing all of the physiologic responses previously described. As a rule, the parasympathetic nervous system must then be suppressed, since the two systems cannot operate simultaneously. The parasympathetic nervous system is stimulated during quiet activities such as eating, which is important because for the body to best use food energy, enzymes and hormones controlling digestion and absorption must be working at their peak performance.

Imagine what goes on in a cortisol-flooded, stressed-out body when food is consumed: Digestion and absorption are compromised, indigestion develops, and the mucosal lining becomes irritated and inflamed. This may sound familiar. Ulcers are more common during stressful times, and many people with irritable bowel syndrome and colitis report improvement in their symptoms when they master stress management.5 And, of course, the resulting mucosal inflammation leads to the increased production of cortisol, and the cycle continues as the body becomes increasingly taxed.4

Cardiovascular Disease
As we’ve seen, cortisol constricts blood vessels and increases blood pressure to enhance the delivery of oxygenated blood. This is advantageous for fight-or-flight situations but not perpetually. Over time, such arterial constriction and high blood pressure can lead to vessel damage and plaque buildup—the perfect scenario for a heart attack. This may explain why stressed-out type A (and the newly recognized type D) personalities are at significantly greater risk for heart disease than the more relaxed type B personalities.6

Fertility Problems
Elevated cortisol relating to prolonged stress can lend itself to erectile dysfunction or the disruption of normal ovulation and menstrual cycles. Furthermore, the androgenic sex hormones are produced in the same glands as cortisol and epinephrine, so excess cortisol production may hamper optimal production of these sex hormones.5

Other Issues
Long-term stress and elevated cortisol may also be linked to insomnia, chronic fatigue syndrome, thyroid disorders, dementia, depression, and other conditions.4,5

Assessing Cortisol Levels
The adrenal stress index (ASI), a salivary test, is the preferred test for adrenal function and a well-accepted, noninvasive, reliable indication of cortisol levels.7-10 However, a trained professional should interpret the results because factors such as age, gender, timing with the menstrual cycle, pregnancy, lactation, smoking, medications, medical conditions, caffeine and alcohol consumption, caloric intake, and other test results (particularly related hormone tests such as sex hormone levels) will contextualize the significance and meaning of the measurement.9,10

The ASI is available as a home kit. Four saliva samples are taken at specific times and then shipped to a laboratory for analysis. Conveniently, in addition to measuring the adrenal hormones cortisol and dehydroepiandrosterone, the same test also measures antibodies to gliadin, often used as a marker for intestinal inflammation, Candida infections, and sensitivity to gluten-containing grains. (Note that this test cannot diagnose gluten sensitivity definitively.)7

A blood cortisol test is available, but it is considered inferior to the salivary test for three reasons: It tests cortisol levels only at one given point in time, which provides less information than levels at four times (which reveals important imbalances) the blood test itself (or simply going to the doctor) can stress a person enough to cause a cortisol surge and it is considered less sensitive because it measures the total hormone level as opposed to specific components.5

The Good News
So far, it may seem as though stressed-out folks are destined for failed health despite their best intentions. Fortunately, there is much we can do for our clients (and ourselves) to reverse the path of destruction. The best approach to keeping cortisol levels at bay is mastering stress management and optimizing diet.

Stress Management
First, regardless of our scope of practice, we can always recommend strategies for effective stress management. Books such as Woodson Merrell’s The Source have some powerful yet commonsense, evidence-based advice for de-stressing and regaining optimal health. Some strategies include getting more and better quality sleep, breath work, acupuncture, cardio/resistance/relaxation exercises, and addressing psychological/emotional issues. Minimizing stress may require a team approach we can acknowledge its importance and leave the details to the experts.

The Anti-Inflammatory Diet
Systemic inflammation, as noted previously, causes elevated cortisol levels. If we can naturally decrease inflammation in the body and minimize stress, decreased cortisol levels should follow, resulting in decreased chronic disease risk and improved wellness. The biochemical processes leading to and abating inflammation are complex and multi-faceted, but as experts in diet and lifestyle, we can make a significant difference.

Like any diet designed to manage a condition, there is no one perfect anti-inflammatory diet. However, based on known properties of foods and clinical research, we can devise a generally low-inflammatory diet and tweak it over time. Obviously, maximizing the anti-inflammatory foods and minimizing the proinflammatory ones is a big step toward controlling inflammation. Incidentally, dietary strategies for controlling inflammation may also help with adrenal support in general, since diet can directly affect adrenal burden (eg, cortisol is released in response to metabolic demands).

Since lifestyle factors are generally the most significant modulators of inflammation, nutrition professionals can make a huge difference in our clients’ and patients’ overall health.4 The following is a general list of diet and lifestyle factors believed to be the most significant contributors to inflammation:

• saturated and trans fatty acids

• insufficient intake of micronutrients and antioxidants

• a sedentary lifestyle and

To minimize inflammation, the following are recommended:

• elimination of trans fats and minimal intake of saturated fats

• elimination or reduction of caffeine

• alcohol in moderation or not at all

• boosting consumption of whole plant foods to maximize intake of fiber, antioxidants, and phytonutrients: with vegetables, fruits, whole intact grains, nuts, seeds, and beans
• meeting recommended intake of omega-3 fatty acids (may be best measured as a ratio to omega-6 fatty acids)

Clearly, these are merely guidelines. Therapeutic nutritional recommendations need to be customized for each individual’s condition, preferences, and goals.

Note that while medications such as nonsteroidal anti-inflammatory drugs temporarily alleviate inflammation, hundreds of studies have demonstrated that long-term use can cause damage over time and even exacerbate systemic inflammation.

Summary
Cortisol is a fascinating hormone that is important to nutrition science on many levels. Understanding the science behind it, including its behaviors and relationships to other biochemical components, the immune system, and health outcomes, is crucial to our success in treating people who seek dietary intervention for stress, illness, fatigue, and other common complaints.

Implementation of targeted dietary and lifestyle approaches is an extremely powerful way to reduce stress, minimize inflammation, and reduce the risk for illness and chronic disease. True, the many biochemical processes involving cortisol and other hormones, stress, and inflammation and their impact on health and disease risk are complex and elaborate. The therapeutic diet and lifestyle strategies, however, are not. The more we learn about the way the body responds to the demands placed on it, as well as its extraordinary healing power, the more we are valued as professionals who can effectively change people’s lives by improving health, inspiring change, and increasing longevity.

— Dina Aronson, MS, RD, owns Welltech Solutions, a nutrition and technology consulting company.

References
1. Andrews RC, Herlihy O, Livingstone DEW, Andrew R, Walker BR. Abnormal cortisol metabolism and tissue sensitivity to cortisol in patients with glucose intolerance. J Clin Endocrinol Metab. 200287(12):5587-5593.

2. Epel ES, McEwen B, Seeman T, et al. Stress and body shape: Stress-induced cortisol secretion is consistently greater among women with central fat. Psychosom Med. 200062(5):623-632.

3. Epel E, Lapidus R, McEwen B, Brownell K. Stress may add bite to appetite in women: A laboratory study of stress-induced cortisol and eating behavior. Psychoneuroendocrinology. 200126(1):37-49.

4. Jones DS, Quinn S (eds). Textbook of Functional Medicine. Gig Harbor, Wash.: Institute for Functional Medicine 2006.

5. Weinstein R. The Stress Effect. New York: Avery-Penguin Group 2004.

6. Sher L. Type D personality: The heart, stress, and cortisol. QJM. 200598(5):323-329.

7. Vining RF, McGinley RA. The measurement of hormones in saliva: Possibilities and pitfalls. J Steroid Biochem. 198727(1-3):81-94.

8. Vining RF, McGinley RA, Maksvytis JJ, Ho KY. Salivary cortisol: A better measure of adrenal cortical function than serum cortisol. Ann Clin Biochem. 198320(Pt 6):329-335.

9. Hellhammer DH, Wust S, Kudielka BM. Salivary cortisol as a biomarker in stress research. Psychoneuroendocrinology. 200934,(2):163-171.

10. Kudielka BM, Hellhammer DH, Wust S. Why do we respond so differently? Reviewing determinants of human salivary cortisol responses to challenge. Psychoneuroendocrinology. 200934(1):2-18.


A nodule (mass) in your adrenal gland or a tumor in the brain’s pituitary gland can trigger your body to make too much cortisol. This can cause a condition called Cushing syndrome. It can lead to rapid weight gain, skin that bruises easily, muscle weakness, diabetes, and many other health problems.

If your body doesn’t make enough of this hormone, you have a condition doctors call Addison’s

disease. Usually, the symptoms appear over time. They include:

  • Changes in your skin, like darkening on scars and in skin folds
  • Being tired all the time
  • Muscle weakness that grows worse , nausea, and vomiting
  • Loss of appetite and weight

If your body isn’t making enough cortisol, your doctor may prescribe dexamethasone, hydrocortisone, or prednisone tablets.

Sources

Hormone Health Network (Endocrine Society): “What Does Cortisol Do?”

Johns Hopkins Medicine: “Adrenal Glands.”

Dartmouth Undergraduate Journal of Science: “The Physiology of Stress: Cortisol and the Hypothalamic-Pituitary-Adrenal Axis.”


PHYSIOLOGICAL EFFECTS OF CORTISOL ON THE ORGANISM

As we have said, cortisol is a hormone that is released in response to physical and emotional stress and acts in order to restore the body’s physiological homeostasis, that is, the balance in many metabolic and immunological areas. Cortisol is neoglucogenic, which means that when there is a decrease in glucose (due to excessive exertion, fasting or excessively low carbohydrate diets) and the body detects that there is a need for it, cortisol is one of the the hormones that are responsible for obtaining glucose from other active ingredients such as fatty acids or muscle amino acids (this process is called neoglucogenesis).

This can lead to a person who has a lot of stress (even with a normal diet in which there is no lack of carbohydrates) end up suffering from hyperglycemia in the plasma, that is, very high levels of glucose as a result of that throughout the day and by being exposed to physical and emotional stress (anxiety, depression, obsessions, etc.), your body releases cortisol and it is producing neoglycogenesis to raise plasma glucose. In the worst case, neoglycogenesis would be carried out through muscle amino acids, so that these people could fall in the long term in a metabolic syndrome caused by the fact that glucose rose more and more. Indirectly and compensatoryly the body could release insulin to lower these glucose levels,

EFFECTS ON COLLAGEN

It has been observed that when there is a release of cortisol, a very high degradation of collagen (protein that can be found in the extracellular matrix) occurs. This would be a dramatic consequence in people or athletes with high cortisol levels as it can lead to injuries.

REGULATION OF MINERALS

Cortisol produces an inhibition regarding the loss of sodium, accumulating this mineral in the extracellular fluid (for example the blood plasma) and causing that when a person is stressed he may end up suffering a secondary blood hypertension. Likewise, cortisol also affects the loss of potassium. By increasing sodium and decreasing potassium, in individuals with an excess of cortisol, there is a greater amount of water, which would explain why we often find cases in which, despite having a correct and balanced diet, certain people have a swollen appearance , with subcutaneous tissues having too much fluid.

IMMUNE SYSTEM AND CORTISOL

Cortisol can produce a downward modulation of the immune system and cause an inhibition in the proliferation of T cells, inhibition in the release of certain interleukins and cytokines, and also a decrease in the release of antibodies. This makes the body dependent on cortisol to deflate any aggressive process that originates in the body (therefore, in cases of allergy or inflammation we usually inject exogenous corticosteroids).

BONE MINERALIZATION AND CORTISOL

It has been observed that this hormone can cause loss of minerals in the bones, which could lead to a lower bone density and long-term osteoporosis.

SEXUAL HORMONAL AXIS

Elevated cortisol generates an inhibition of the sexual hormonal axis, so that prolactin increases and there is a decrease in GNRH and gonadotropins LH and FSH. In short: a decrease in the release of testosterone by the testicle, or progesterone and estrogen in the ovary, which evidently influences both sports performance and fertility.

THYROID FUNCTION

People who suffer from long periods of stress with cortisol release, are at risk of reaching times when the body decompensate and suffer from hypothyroidism.

DIGESTIVE SYSTEM

It is important to know that every time the gastric mucosa is inflamed or irritated, when we take high amounts of protein or we are exposed to gluten or dairy, the body can generate a release of cortisol looking for a digestive and intestinal inflammation. The price to pay is that the large amounts of cortisol favor the appearance of the intestinal permeability syndrome. In the long term, it would destabilize the flora and generate alterations at the immunological level as a result of the passage of toxins from the intestinal lumen to the blood plasma.


Sounding the alarm

The stress response begins in the brain (see illustration). When someone confronts an oncoming car or other danger, the eyes or ears (or both) send the information to the amygdala, an area of the brain that contributes to emotional processing. The amygdala interprets the images and sounds. When it perceives danger, it instantly sends a distress signal to the hypothalamus.

Command center

When someone experiences a stressful event, the amygdala, an area of the brain that contributes to emotional processing, sends a distress signal to the hypothalamus. This area of the brain functions like a command center, communicating with the rest of the body through the nervous system so that the person has the energy to fight or flee.

The hypothalamus is a bit like a command center. This area of the brain communicates with the rest of the body through the autonomic nervous system, which controls such involuntary body functions as breathing, blood pressure, heartbeat, and the dilation or constriction of key blood vessels and small airways in the lungs called bronchioles. The autonomic nervous system has two components, the sympathetic nervous system and the parasympathetic nervous system. The sympathetic nervous system functions like a gas pedal in a car. It triggers the fight-or-flight response, providing the body with a burst of energy so that it can respond to perceived dangers. The parasympathetic nervous system acts like a brake. It promotes the "rest and digest" response that calms the body down after the danger has passed.

After the amygdala sends a distress signal, the hypothalamus activates the sympathetic nervous system by sending signals through the autonomic nerves to the adrenal glands. These glands respond by pumping the hormone epinephrine (also known as adrenaline) into the bloodstream. As epinephrine circulates through the body, it brings on a number of physiological changes. The heart beats faster than normal, pushing blood to the muscles, heart, and other vital organs. Pulse rate and blood pressure go up. The person undergoing these changes also starts to breathe more rapidly. Small airways in the lungs open wide. This way, the lungs can take in as much oxygen as possible with each breath. Extra oxygen is sent to the brain, increasing alertness. Sight, hearing, and other senses become sharper. Meanwhile, epinephrine triggers the release of blood sugar (glucose) and fats from temporary storage sites in the body. These nutrients flood into the bloodstream, supplying energy to all parts of the body.

All of these changes happen so quickly that people aren't aware of them. In fact, the wiring is so efficient that the amygdala and hypothalamus start this cascade even before the brain's visual centers have had a chance to fully process what is happening. That's why people are able to jump out of the path of an oncoming car even before they think about what they are doing.

As the initial surge of epinephrine subsides, the hypothalamus activates the second component of the stress response system — known as the HPA axis. This network consists of the hypothalamus, the pituitary gland, and the adrenal glands.

The HPA axis relies on a series of hormonal signals to keep the sympathetic nervous system — the "gas pedal" — pressed down. If the brain continues to perceive something as dangerous, the hypothalamus releases corticotropin-releasing hormone (CRH), which travels to the pituitary gland, triggering the release of adrenocorticotropic hormone (ACTH). This hormone travels to the adrenal glands, prompting them to release cortisol. The body thus stays revved up and on high alert. When the threat passes, cortisol levels fall. The parasympathetic nervous system — the "brake" — then dampens the stress response.


Mechanism

The release of cortisol is under control of the hypothalamus-pituitary-adrenal (HPA) axis. Corticotropin-releasing hormone (CRH) is released by the paraventricular nucleus (PVN) of the hypothalamus.[2] It then acts on the anterior pituitary to release adrenocorticotropic hormone (ACTH), which subsequently acts on the adrenal cortex. In a negative feedback loop, sufficient cortisol inhibits the release of both ACTH and CRH. The HPA axis follows a circadian rhythm. Thus, cortisol levels will be high in the morning and low at night [2].

Steroid hormones, such as cortisol, are primary messengers. They can cross the cytoplasmic membrane because of their fat-soluble properties. Cell membranes are composed of phospholipid bilayers these prevent fat-insoluble molecules from passing through. Once cortisol passes through the cell membrane and enters into the cell, it binds to specific receptors in the cytoplasm. In the absence of cortisol, the glucocorticoid receptor binds to an Hsp90 chaperone protein in the cytosol. The binding of cortisol to the glucocorticoid receptor dissociates the Hsp90. The cortisol-receptor complex then enters the nucleus of the cell and affects gene transcription.


Yale study solves mystery of how stress triggers inflammation

A new Yale University-led study has solved a long-standing mystery of how acute stress seems to amplify inflammatory disease despite the fact many stress hormones actually suppress the immune system. The research reveals a particular immune cell is released by fat cells when an organism faces systemic stress.

For several decades a link between stress and inflammatory disease has been clear, with many chronic diseases obviously triggered into flare-ups by acute periods of stress. However, underlying this clear observation has been an unexplained paradox hormones released by the body in the face of stress, such as cortisol and adrenaline, confer distinctly immunosuppressive effects, yet stress somehow still seems to stimulate inflammation.

“In the clinic, we have all seen super-stressful events that make inflammatory disease worse, and that never made sense to us,” explains corresponding author on the study, Andrew Wang.

The new study stemmed from a novel laboratory observation. Taking blood samples from mice is an inherently stressful procedure and the researchers noticed this correlated with an increase in interleukin-6 (IL-6) levels. Increased IL-6 levels have previously been implicated in autoimmune conditions and acute stress, but exactly how it is released has not been studied.

The results of the new research, described as “completely unexpected” by one of the authors, reveal IL-6 is secreted by brown fat cells in the face of acute stress. It’s this immune mechanism that amplifies inflammation when we face a stressful situation. And, when signaling between the brain and brown fat cells was blocked in mice, the animals no longer showed inflammatory responses when presented with stressful situations.

But one question still remained unanswered – what evolutionary function explains why stress triggers such a damaging immune system mechanism?

Here, the researchers discovered IL-6 plays a fundamental role in mediating hypoglycemia. Essentially, this helps prepare the body for increases in glucose production necessary as fuel for our “fight or flight” response. The study explains, from an evolutionary perspective, “this adaptation comes at the cost of enhancing mortality to a subsequent inflammatory challenge.”

Therefore, these findings offer compelling and novel research pathways, not only for a number of autoimmune conditions, but also for many mental health disorders. When IL-6 was blocked in the mice the animals displayed significant reductions in signs of agitation, suggesting the immune mechanism may play a role in anxiety and depression.

IL-6-inhibiting drugs already exist, and have been used to treat autoimmune conditions such as rheumatoid arthritis. Tocilizumab, the first FDA-approved IL-6 inhibitor, is already being trialed as an anti-depressant therapy.


Introduction

Stress is a broad concept that comprises challenging or difficult circumstances (stressors) or the physiological or psychological response to such circumstances (stress responses). In humans, among other species, one of the systems that responds to challenging circumstances is the immune system. Broadly, the immune system comprises cells, proteins, organs, and tissues that work together to provide protection against bodily disease and damage (see Box for explanations of relevant immunological parameters). Several facets of the human immune system have been empirically associated with stress. During acute stress lasting a matter of minutes, certain kinds of cells are mobilized into the bloodstream, potentially preparing the body for injury or infection during 𠇏ight or flight” [1]. Acute stress also increases blood levels of pro-inflammatory cytokines [2]. Chronic stress lasting from days to years, like acute stress, is associated with higher levels of pro-inflammatory cytokines, but with potentially different health consequences [3]. Inflammation is a necessary short-term response for eliminating pathogens and initiating healing, but chronic, systemic inflammation represents dysregulation of the immune system and increases risk for chronic diseases, including atherosclerosis and frailty [4]. Another consequence of chronic stress is activation of latent viruses. Latent virus activation can reflect the loss of immunological control over the virus, and frequent activation can cause wear-and-tear on the immune system [5].

Interestingly, these responses may not be the same for everyone. Those who have experienced early adversity, for example, may be more likely to exhibit exaggerated immune reactions to stress [6, 7]. Currently, the field is moving toward a greater understanding of who might be most at risk for chronic inflammation and other forms of immunological dysregulation, and why. This question is important not only for health, but also for longevity, as evidence suggests that the immunological effects of chronic stress can advance cellular aging and shorten telomere length [8].

Meta-analyses provide a look backward at this research and summarize what has been learned about the relationship between stress and human immunity since it was first studied in the 1960s [1, 2, 9]. This review describes recent, groundbreaking work on the stress-immune relation in humans, including the immunological consequences of stress in early and late life, mediators of the stress-immunity link, ecological perspectives, and how the relationship between stress and immunity is manifest in clinical populations (see Figure ).

Stress, immunity, and disease can affect each other in reciprocal ways, but these relationships can be moderated by life stage, other ecological pressures and goals, stressor duration, and protective factors such as good sleep.

Early life stress

Stress that occurs early in development (e.g., maltreatment, poverty, and other adverse experiences) has immunological consequences that can be observed both in the near and long term after the stressor occurs. Early life stress (ELS) in children associates with immunological dysregulation, including low basal levels of cytokines that control immune responses [10]. When immune cells were stimulated in vitro (e.g., with tetanus toxoid), those cells from children who experienced ELS produced more pro-inflammatory cytokines [10]. Whereas much of the extant research focuses on maltreatment or poverty, a recent study into the effects of a less-studied adversity, bullying, also suggests that chronic peer victimization predicts a steeper increase in CRP from childhood into young adulthood [11]. EBV antibody levels in a younger adult sample were also found to differ based on the type, timing, and frequency of exposure to ELS. Individuals exposed to sexual abuse more than 10 times, as well as those physically abused starting between ages 3 and 5, had elevated levels of antibodies against EBV as adults, a signal of viral reactivation [12]. In adults, a meta-analysis of ELS and inflammation found a positive association between maltreatment and several inflammatory markers, with the most robust association for circulating CRP [13]. Recent work has investigated mechanisms linking ELS to immune alterations over time (e.g., self-control, adiposity, smoking, and stress 14, 15] as well as examining inflammatory dysregulation as a pathway through which ELS affects adult disease prevalence and outcomes [16]. Finally, empirically based interventions to target immunological consequences of ELS are a necessary next step recent evidence suggests the plausibility of such interventions to improve inflammatory profiles for youth raised in low-income families [17].

Stress, immunity, and aging

As people age, they are less able to mount appropriate immune responses to stressors. These could be physical stressors, such as injury, or psychological stressors such as caregiving. In addition, psychological stress affects organisms in a manner similar to the effects of chronological age, and chronological aging coupled with chronic stress accelerates immunological aging [18]. Research has suggested that older adults are unable to terminate cortisol production in response to stress. Cortisol is ordinarily anti-inflammatory and contains the immune response, but chronic elevations can lead to the immune system becoming “resistant,” an accumulation of stress hormones, and increased production of inflammatory cytokines that further compromise the immune response [18]. Older adults often have to provide long term care for an ailing spouse or partner. Caregiving has been implicated in significantly lower antibody and cell-mediated immune responses after vaccination [19, 20]. Caregivers also experience longer wound healing times, lower lymphocyte proliferation, increased proinflammatory cytokine levels, and more reactivation of latent viruses [21].

An important direction in aging research involves an examination of telomeres. Telomere length has been used as a measure of biological aging and is associated with psychological, physiological, and social factors. Chronic stress is linked to shortened telomere length along with increased disease in older adults [22]. Socioeconomic factors such as marital status and income have been linked with telomere length: those married for longer periods of time and who make more money are biologically younger than others in their cohort [22, 23]. However, studies thus far have found this link only in Caucasians and Hispanics, but not African Americans. This suggests that low socioeconomic status (SES) may accelerate aging in some populations [23]. Interestingly, health behaviors can moderate this effect by protecting individuals from accelerated aging during stress exposure [24]. It is unclear how this moderation occurs, and more work is needed.

Collectively, recent work points to new discoveries into how biological aging and stress interact to influence the immune response. This will lead to a better understanding of mechanisms of immunosenescence caused by stress and chronological aging that are presently unclear.

Biological and behavioral mediators of the relationship between stress and immunity

How does stress get “under the skin” to influence immunity? Immune cells have receptors for neurotransmitters and hormones such as norepinephrine, epinephrine, and cortisol, which mobilize and traffic immune cells, ideally preparing the body to mount an immune response if needed [25]. Recent evidence shows that immunological cells (e.g., lymphocytes) change their responsiveness to signaling from these neurotransmitters and hormones during stress [26]. However, immunological responses are biologically and energetically costly, and over time, chronic stress produces negative systemic changes both in immune trafficking and in target tissues [6].

The linkages between stress and immunity may be mediated by specific health behaviors, psychosocial factors, or both. For instance, stress has been linked to being in troubled relationships, having negative or competitive social interactions, and feeling lonely, which have each in turn been linked to increases in pro-inflammatory responses to stress [27-29]. Other potential mediators, like getting good sleep, are increasingly being recognized as important pieces of the stress-immunity puzzle [30]. Even one night of total sleep deprivation was recently found to significantly increase neutrophil counts and decrease neutrophil function in healthy men [31].

Taken together, these examples highlight a better understanding of the factors that mediate or moderate stress's influence on immunity. This direction may serve to one day develop targeted behavioral or pharmacotherapies to those at highest risk for poor health outcomes.

Ecological immunology

Over the last several years, there has been greater attention paid to the relevance of ecological immunity to the relationship between stress and immunity. Ecological immunity is based on the premise that mounting immune responses is energetically costly and that the (mal)adaptiveness of immune responses to stress is determined by cost:benefit ratios [32-34]. In early human history many stressors were life-threatening: being eaten by a predator, being excluded by one's peer group, or being faced with starvation, to name a few. Appropriately responding to some of these stressors (e.g., predation) required activating the energetically costly fight or flight response, including immunological changes that could protect against infection secondary to wounding. However, energetic costs of the immune system during other kinds of stressors (e.g., social exclusion) that resulted in less availability of energetic resources (e.g., shared food) might have been counterproductive. Thus, downregulating immune responses might have been evolutionarily adaptive. Research in bumblebees finds that under conditions of starvation, immune responses to an immune challenge accelerated time to death from starvation, suggesting that allocating energy to the immune system under those conditions was maladaptive [35]. Although energetic resources are abundant in the modern environment, physiological evidence of these ecological tradeoffs in the ancestral environment can still be found. For example, in contemporary humans, costly endeavors such as building and maintaining a large social network or persisting on unsolvable challenges can be associated with decreases in some immune parameters [36, 37]. Taken together, these and other findings [for reviews, see 33, 38] suggest that ecological conditions and resource availability may shape immune functioning in ways that remain relatively underexplored.

Stress, immunity, and clinical health

Psychological stress has been implicated in altered immune functioning in many diseases. Stress induces chronic immune activation and altered health outcomes that resemble those seen in chronic inflammatory diseases such as RA [39, 40]. Altered immune function can lead to exacerbated symptoms of both physical and psychological illnesses. In irritable bowel syndrome, sustained cortisol activity during stress is associated with an increase in gastrointestinal symptoms [41]. High levels of proinflammatory cytokines resulting from stress have recently been implicated in the etiology of schizophrenia and schizophrenia-related brain alterations [42]. Chronic stress has been shown to enhance risk for developing autoimmune disease [e.g., 43]. Individuals with autoimmune disease also appear to have difficulty down-regulating their immune responses after exposure to stressors. In MS, neuropeptides secreted under stress (e.g., corticotropin-releasing hormone) activate glial cells in the brain to release inflammatory molecules that result in brain inflammation and worsen MS pathology [44]. Similar immune activation and symptom exacerbation is evidenced in those with other autoimmune diseases [40]. Currently, possible mechanisms by which autoimmune diseases alter individual responses to stress are being explored. This knowledge may lead to interventions that decrease stress-induced immune responses and improve outcomes in autoimmune diseases.

Conclusions and future directions

Research on the immunological effects of stress has burgeoned over the past decade following Segerstrom and Miller's meta-analysis [1]. This research has explored new avenues, including the areas reviewed here, that show particular promise for illuminating the conditions under which stress impacts the immune system. Research on stressors occurring early (i.e., childhood and adolescence) and late (i.e., aging) in the lifespan have suggested that individuals exposed to chronic stressors (e.g., abuse, caregiving) can exhibit immune dysregulation that may be persistent and severe. Stressor qualities (e.g., type, timing) as well as individual characteristics that make individuals more or less susceptible to these effects are targets for future work. Examinations of mediators and mechanisms of the stress-immune relation can also determine how and for whom exposure to stress impacts the immune response. Ecological immunology suggests that downregulating the immune response may sometimes be adaptive, and future work building from this perspective will help to further elucidate contexts in which immunosuppression may occur but progress toward superordinate goals is facilitated. Finally, research into the effects of stress on inflammation in clinical populations has demonstrated that stress exposure can increase the likelihood of developing disease, as well as exacerbating preexisting conditions. Further work in this area may help to treat or even prevent morbidity. Overall, this area of research is broad, rapidly developing, and holds promise for improving human health.

Box: Guide to some immunological parameters related to stress

Antibodies: Proteins produced by immune cells that can bind to pathogens such as viruses, bacteria, and parasites. Bound pathogens are inactivated or marked for killing by other immune cells.

Autoimmune disease: Caused when the immune system misidentifies self tissue as foreign and mounts an attack against it. Examples include rheumatoid arthritis (RA), lupus, and multiple sclerosis (MS).

C-reactive protein (CRP): A downstream product of pro-inflammatory signaling and marker of systemic inflammation.

Cell-mediated immunity: The arm of the immune system that protects against pathogens residing inside cells (e.g., viruses) and other “sick” cells such as cancer cells.

Cortisol: A steroid hormone produced by the adrenal gland with broad metabolic effects, including suppression of some facets of the immune system.

Cytokines: Proteins that coordinate immune responses. Examples include interleukins (IL). Some cytokines, such as IL-5 and IL-10, primarily control and contain immune responses. Others, such as IL-6 and tumor necrosis factor-α (TNF-α), induce inflammation.

Inflammation: Local inflammation is a part of the healing process that includes accumulation of immune cells, anti-pathogen activity, and initiation of tissue repair. Chronic, systemic inflammation, in contrast, can promote tissue damage across a number of systems.

Latent viruses: Viruses that reside in the body indefinitely after infection, often without overt disease consequences either acutely or chronically. Examples include Epstein-Barr virus (EBV) and cytomegalovirus (CMV).

Neutrophils: The first cells to infiltrate damaged or infected tissue and effect an inflammatory response.

Telomeres: The protective caps on the end of chromosomes that prevent deterioration.

Highlights

Psychological stress can dysregulate the human immune system.

Stress can impact immunity differentially across individuals and contexts.

Recent work in this area has made strides towards elucidating these differences.

Future work holds promise for reducing stress's effects on physical health.


Stress Essential Reads

It’s Time to Talk About the Privilege of Self-Care

Dealing With a Stressful Situation When All Alone

Example of Mindfulness and Loving-Kindness Meditation (LKM) method.

I like to practice two types of meditation in one 15-minute session. Personally, I like to use a timer and an “Om” or “Aum” track I have on my iTunes. Some purists might call this "sacrilege," but it works for me, and it might work for you.

To begin, I jot down the names of people I know who are struggling or suffering on a notecard. Next, I set my iPhone to a 15-minute countdown that ends in a harp sound. Then, I sit upright in a chair with my legs crossed at the ankles, set the timer, start the Om/Aum track, and sit with my palms open and facing upwards on my knees.

I begin with a mindfulness meditation of simply focusing on my breath and repeating my "mantra," which is three words that resonate with me. You can choose any word or combination of words that have meaning and significance to you. I repeat these words silently in my mind like a rosary, as I take deep breaths, relax my shoulders, and feel myself drift into a trance-like state.

After a few minutes, I move into the Loving-Kindness Meditation (LKM) phase, which has three steps for me. First, I go through the checklist of specific people I know who are struggling, suffering (or frustrating me), and send them love, light, strength, and compassion. Secondly, I move to universal thoughts of loving-kindness for strangers I may have read about in the news or larger populations that are suffering. Thirdly, as part of the LKM phase, I focus on self-compassion and forgive myself for my "trespasses" and ask for atonement.

After I’ve completed the LKM cycle, I return back to a single-focused meditation, emptying my mind and focusing on my breathing until the alarm goes off. When I hear the harp sound, there is always a Pavlovian-conditioned response of an "ahhh" feeling, accompanied by a big exhale, as I open my eyes and face the real world again.

Remember, you can meditate anytime and any place. Mindfulness meditation is a powerful de-stressor and cortisol reducer that is always in your toolbox and at your fingertips. You can squeeze in a few minutes of meditation on the subway, in a waiting room, on a coffee break.

3. Social Connectivity. Two studies published this week in Science illustrate that social aggression and isolation lead to increased levels of cortisol in mice, which trigger a cascade of potential mental health problems — especially in adolescence.

Researchers at Johns Hopkins established that elevated levels of cortisol in adolescence change the expression of numerous genes linked to mental illness in some people. They found that these changes in young adulthood (a critical time for brain development) could cause severe mental illness in those predisposed for it. These findings, reported in the January 2013 issue of Science, could have wide-reaching implications in both the prevention and treatment of schizophrenia, severe depression, and other mental illnesses.

Akira Sawa, a professor of psychiatry at the Johns Hopkins University School of Medicine, and his team set out to simulate the social isolation associated with the difficult years of adolescence in human teens. They found that isolating mice known to have a genetic predisposition for mental illness during their adolescence triggered "abnormal behaviors" that continued even when they were returned to the group. They found that the effects of adolescent isolation lasted into the equivalent of mouse adulthood.

"We have discovered a mechanism for how environmental factors, such as stress hormones, can affect the brain's physiology and bring about mental illness," said Sawa. "We've shown in mice that stress in adolescence can affect the expression of a gene that codes for a key neurotransmitter related to mental function and psychiatric illness. While many genes are believed to be involved in the development of mental illness, my gut feeling is environmental factors are critically important to the process."

To shed light on how and why some mice got better, Sawa and his team studied the link between cortisol and the release of dopamine. Sawa says the new study suggests that we need to think about better preventative care for teenagers who have mental illness in their families, including efforts to protect them from social stressors, such as neglect. Meanwhile, by understanding the cascade of events that occurs when cortisol levels are elevated, researchers may be able to develop new compounds to target tough-to-treat psychiatric disorders with fewer side effects.

In another study published in Science, French researchers revealed that mice subjected to aggression by specific mice bred to be "bullies" released cortisol, which triggered a response that led to social aversion to all other mice. The exact cascade of neurobiological changes was complex, but also involved dopamine. The researchers found that if they blocked the cortisol receptors, the bullied mice became more resilient and no longer avoided their fellow creatures.

Close-knit human bonds — whether it be family, friendship, or a romantic partner — are vital for your physical and mental health at any age. Recent studies have shown that the Vagus nerve also responds to human connectivity and physical touch to relax your parasympathetic nervous system.

The “tend-and-befriend” response is the exact opposite to “fight-or-flight.” The "tend-and-befriend" response increases oxytocin and reduces cortisol. Make an effort to spend real face-to-face time with loved ones whenever you can, but phone calls and even Facebook contact can reduce cortisol if they foster a feeling of genuine connectivity.

4. Laughter and Levity. Having fun and laughing reduces cortisol levels. American psychiatrist William Fry has found links to laughter and lowered levels of stress hormones. Many studies have shown the benefits of having a sense of humor, laughter, and levity. Try to find ways in your daily life to laugh and joke as much as possible, and you'll lower cortisol levels.

5. Music. Listening to music that you love, and that fits the mood you're in, has been shown to lower cortisol levels. I recently wrote here about the wide range of benefits that come from listening to music. We all know the power of music to improve mood and reduce stress. Add reducing your cortisol levels as another reason to keep the music playing as a soundtrack of health and happiness in your life.

President Obama’s second inaugural speech brought up many calls to action that can be framed through the lens of "Cortisol as Public Health Enemy Number One." The ripple effect of a fearful, isolated, and stressed-out society increases cortisol levels across the board for Americans of all ages. This creates a public health crisis and a huge drain on our economy.

If each of us works alone, and together, to reduce cortisol levels, we will all benefit. As citizens, if we live like we are "All for one, and one for all," we can reduce the amount of stress hormone in our society and individual lives.

Feeling socially connected, safe, and self-reliant reduces cortisol. I hope these tips will help you make lifestyle choices that reduce your levels of stress hormone.

Lastly, in light of the Sandy Hook tragedy, we are all looking for components to a multi-pronged approach that will stop the violence and bloodshed. In my opinion, one way to do this is to create public health policies and funding aimed specifically at reducing cortisol levels in American youth.

In Obama’s speech, he declared, “Our journey is not complete until all of our children, from the streets of Detroit, to the hills of Appalachia, to the quiet lanes of Newtown, know that they are cared for, and cherished, and always safe from harm.” Beyond talk of gun violence legislation, if our legislators and business leaders strive to create policies and fund initiatives that create social connectivity among at-risk teens and reduce bullying, they will be reducing cortisol levels in young people. This should make them mentally and physically healthier, more resilient, and less likely to be violent.


Watch the video: Cortisol protein catabolism, gluconeogenesis, vasoconstriction u0026 anti-inflammation (January 2023).