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• Mouse study suggests that interleukin-6-releasing immune cells outside the brain influence the propensity to develop depression. (2013) www.sciencedaily.com
  Brain Inflammation Depression IL-6

  Psychosocial stress promotes the release of IL-6, potentially driving the development of depression.

  Psychosocial stress, such as that experienced with divorce, discrimination, trauma, or the death of a child, can have profound effects on the human body. For example, evidence indicates that stress alters the immune system, driving inflammatory processes and impairing antiviral responses. Findings from a 2013 study suggest that psychosocial stress promotes the release of interleukin 6 (IL-6), potentially driving the development of depression.

  IL-6 is a pro-inflammatory cytokine that plays an important role as a mediator of fever and the body’s immune response. It is produced by almost all immune cells and is induced in the context of infection, autoimmunity, or cancer. Many physiological processes are influenced by IL-6, including glucose metabolism, blood cell production, neuroendocrine regulation, and fatigue, among others. IL-6 levels are often elevated in people who have depression.

  The investigators conducted their study using mice that had undergone radiation to destroy their bone marrow, compromising their immune function. Then they transplanted bone marrow from mice that exhibited either high or low levels of IL-6 levels in response to stress into the immune-compromised animals. Then they exposed the animals to a social stressor.

  They found that mice that received transplants from those that exhibited high IL-6 levels in response to stress demonstrated more depression-like behaviors than the mice that received transplants from those that exhibited low IL-6 levels. These findings suggest that IL-6 promotes a pro-inflammatory state that promotes depression-like symptoms in response to psychosocial stress. Identifying therapeutic strategies that inhibit IL-6 may benefit people who are vulnerable to the effects of psychosocial stress.

  Interestingly, hyperthermia, such as that experienced with sauna use or hot baths, has been shown to reduce IL-6 levels. Learn more about the beneficial effects of sauna use in our overview article.

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  • Learn more about depression in our overview article.
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• Microglial interleukin-6 signaling and prostaglandin synthesis may regulate depressive symptoms in neurological disorders. (2021) www.sciencedaily.com
  Brain Inflammation Depression Mental Health IL-6

  Microglia and IL-6 drive the negative mood often associated with inflammation.

  People who have certain neurological disorders, such as Alzheimer’s disease, Parkinson’s disease, or stroke, often exhibit low mood. Evidence suggests that inflammation plays a role in the pathogenesis of these neurological disorders and likely influences mood, as well. Findings from a 2021 study suggest that microglia activation drives the low mood often associated with neurological disorders.

  Microglia are the brain’s resident immune cells. They serve an essential role in maintaining brain microenvironment homeostasis. Acute activation of microglia modulates inflammation and neurotoxicity, but chronic activation promotes brain inflammation and damage. Evidence suggests that microglia activation influences mood.

  The investigators used chemogenetics, a research technique that uses drugs or other chemicals to modulate neural activity, to stimulate microglia activation in the brains of mice. They noted that levels of interleukin-6 (IL-6, a pro-inflammatory cytokine) and prostaglandins (hormone-like molecules that are involved in inflammation) increased in the animals' brains. In addition, the animals exhibited a low mood. Blocking microglia activity restored the animals' positive mood, however.

  These findings suggest that microglia drive the low mood often associated with inflammation and that IL-6 is a prominent player in this process. Learn more about the role of inflammation and mood in this episode featuring Dr. Charles Raison.

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• In a mendelian randomization study, genetically predicted levels of interleukin 6 (IL-6) were associated with neuropsychiatric disorders. www.sciencedaily.com
  Brain Inflammation Mental Health Genetics IL-6

  IL-6 may drive inflammation in neuropsychiatric disorders.

  Neuropsychiatric disorders are the leading cause of disability among people living in the United States, accounting for nearly 20 percent of all years of life lost to disability and premature death. Evidence suggests that brain inflammation is a key player in neuropsychiatric disorders, the effects of which may be bidirectional. A recent study identified potential links between inflammation and structural alterations in regions of the brain implicated in neuropsychiatric disorders.

  The brains of people with neuropsychiatric disorders exhibit a range of abnormal structural alterations, but researchers don’t fully understand what drives these abnormalities. One possible player is interleukin-6 (IL-6), a cytokine that can cross the blood-brain barrier, increasing the barrier’s permeability and promoting brain inflammation. In turn, this inflammation can impair synaptic pruning, a natural process that occurs in the brain between early childhood and adulthood and eliminates extra synapses. Inappropriate synaptic pruning is associated with some neuropsychiatric disorders, including schizophrenia and autism.

  The investigators searched for evidence of potential causality in the association between inflammatory cytokines and altered brain structure using Mendelian randomization, a research method that provides evidence of links between modifiable risk factors and disease based on genetic variants within a population. Using data from more than 20,000 adults enrolled in the UK Biobank study, the researchers looked for associations between genetic variants that influence levels of interleukin-6 (IL-6, a pro-inflammatory cytokine), as well as other inflammatory factors. and changes in gray matter volume in specific areas of the brain. They also examined postmortem brain tissue to assess gene expression in the brain areas of interest.

  They found that genes that influence the production of pro-inflammatory molecules, especially IL-6, are strongly linked with brain structure in the temporal and frontal regions of the brain, areas of the brain commonly implicated in neuropsychiatric disorders. The postmortem analyses revealed that the overproduction of these pro-inflammatory genes is associated with disorders such as epilepsy, cognitive disorder, schizophrenia, psychotic disorder, and autism spectrum disorder.

  These findings suggest that pro-inflammatory pathways, especially those associated with IL-6, are essential for normal brain structural development and IL-6 elevation may drive structural alterations implicated in neuropsychiatric disorders. Evidence suggests that heat stress reduces symptoms associated with depression, a type of neuropsychiatric disorder. Learn about a clinical trial that is investigating the benefits of heat stress in this episode featuring Dr. Ashley Mason.

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• Low levels of interleukin-6 (IL-6) in the prefrontal cortex enhanced reversal learning in rats. (2014) www.sciencedaily.com
  Brain IL-6

  Cytokine signaling in the brain promotes cognitive flexibility.

  Cytokines are small signaling proteins that play essential roles in the body’s inflammatory process. They are produced primarily by immune cells, but they are also produced at basal levels in the brain, where they participate in memory and learning. Findings from a 2014 study suggest that cytokine signaling in the brain is necessary for reversal learning.

  Reversal learning is a form of cognitive flexibility. It allows an organism to determine that a reward for a particular activity has changed and then adjust its behavior accordingly. Reversal learning enables an organism to disengage from ongoing behavior, a quality that is related to impulsive or compulsive actions. Evidence suggests that reversal learning is impaired in neuropsychiatric disorders such as depression, schizophrenia, and obsessive-compulsive disorder.

  The researchers conducted a three-part experiment. First, they blocked the production of interleukin-6 (IL-6), a type of cytokine, in the brains of rats. They subjected one-half of the rats to cold stress (which has been shown to impair reversal learning), and the other half was left in a non-stressful environment. Then they tested both the stressed and non-stressed animals' reversal learning capacities. Surprisingly, they found that blocking IL-6 impaired reversal learning in both groups of animals, suggesting that basal IL-6 activity in the brain (in the absence of stress or inflammation) may aid learning.

  In their second experiment, the researchers determined that IL-6 is produced in the orbitofrontal cortex, a region of the brain responsible for decision-making and learning. They also determined that the mechanism by which IL-6 facilitates reversal learning was a signaling pathway called JAK/STAT, which is involved in multiple physiological processes.

  Finally, they restored IL-6 levels in the orbitofrontal cortex region of the animals' brains. They subjected them to cold stress again and re-tested their reversal learning capacities. They found that restoring IL-6 to the animals' brains attenuated the stress-induced reversal learning losses.

  These findings suggest that a basal level of the cytokine IL-6 is essential for reversal learning in rats. The researchers posited that although IL-6 is typically a pro-inflammatory cytokine, it may exert differential effects under different conditions. For example, it may promote learning deficits under inflammatory conditions, but facilitate learning under basal (non-stressed, non-inflammatory) conditions.

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• Obese when compared to those with normal body fat had much higher inflammation: 53% higher CRP, 30% higher TNF-a, 17% higher WBC count, 42% higher IL6 linkinghub.elsevier.com
  Obesity Aging Metabolism Inflammation Immune System Metabolic Syndrome IL-6

  Strong link between accumulated visceral fat and chronic inflammation.

  A person’s waist-to-hip ratio compares their waist measurement to that of their hips. A high ratio can be an indicator of excess fat accumulation around the waist, often referred to as visceral fat. Findings from a 2005 study suggest that visceral fat is associated with markers of inflammation.

  Visceral fat is stored in the abdominal cavity near the liver, pancreas, and intestines. The accumulation of visceral fat is linked to increased risk of cardiovascular disease and other chronic diseases. Many factors drive visceral fat accumulation, including poor sleep, an obesogenic diet, and sugar-sweetened beverage intake, among others.

  The study involved more than 3,000 healthy males and females (18 to 89 years old) living in Greece. The investigators calculated the participants' body mass index (BMI) and measured their waist and hip circumferences. Participants provided blood samples for the assessment of inflammatory biomarkers, including C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-alpha), amyloid A (an apolipoprotein secreted in the acute stage of inflammation), white blood cells, and interleukin-6 (IL-6).

  The investigators found that approximately 36 percent of the males and 43 percent of the females had excess visceral fat. Approximately 20 percent of the males and 15 percent of the females had obesity. Participants with greater visceral fat had 53 percent higher CRP, 30 percent higher TNF-alpha), 26 percent amyloid A, 17 percent higher white blood cell counts, and 42 percent higher IL-6, compared to participants with normal fat distribution. The relationship between visceral fat and inflammatory markers was stronger than that between obesity and inflammation, even when considering the participants' age, income, education, and other potential confounding factors.

  These findings suggest that visceral fat and inflammatory processes are linked. The investigators posited that excess accumulation of visceral fat may increase the risk for cardiovascular disease by driving inflammation.

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• Muscle produces tumor-suppressing compounds during exercise in men with prostate cancer. www.ecu.edu.au
  Exercise Cancer IL-6

  Exercise oncology is an emerging branch of medicine that studies the application of exercise medicine in the treatment of cancer. Although there is a strong base of epidemiological research that supports a relationship between increased physical activity and decreased cancer severity and death, the molecular mechanisms that underlie this relationship require further research. Findings of a recent report identify myokines that suppress tumor growth in patients with prostate cancer.

  Myokines are molecules released from muscle cells that signal to non-muscle tissues that the body is physically active. Studies in non-human animals have shown that myokines such as oncostatin M, decorin,, and interleukin (IL)-6 suppress cancer growth; however research in humans is lacking.

  The investigators recruited 10 men (average age, 73 years) with prostate cancer who were undertaking androgen deprivation therapy, which includes drugs that block the action of testosterone and other male hormones. Participants completed 12 weeks of exercise training that included three sessions-per-week of supervised resistance training and daily self-directed moderate-to-vigorous physical activity. The investigators measured the participants' muscle strength, body composition, and serum myokine concentration before and after the exercise training intervention. They also grew prostate cancer cells in vitro, exposed them to serum from participants taken before and after exercise training, and observed the effects on cancer cells directly.

  Participants lost about six pounds of fat and eight pounds of total body weight during the intervention period. Participants significantly increased their strength, measured during the leg press (57 pound increase) and chest press (16 pound increase). Serum concentrations of oncostatin M increased by 82 percent while other myokines did not increase or could not be measured. Finally, prostate cancer cells incubated with serum taken post-exercise training reduced cancer growth by 22 percent compared to serum taken prior to exercise training.

  These results show that exercise induced the expression of myokines with tumor-suppressing ability in patients with prostate cancer. Future research is needed to refine the prescription of intensity, frequency, and type of exercise in cancer treatment.

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