Adaptation is one of the core characteristics of living organisms, wherever it refers to proximate adjustments at individual level to inner or outer events, or to ultimate evolutionary processes at species-level. Biology and medicine have for a long time considered the non-specific symptoms of sickness i.
Considering that living organisms have always lived surrounded by pathogenic microorganisms and will continue to do so, it has been proposed that non-specific symptoms of infection and inflammation could represent specific forms of adaptation to the presence of systemic protozoa, bacteria or viruses . Indeed, throughout their evolutionary history, all species have been exposed to, and have successfully resisted the noxious effects of various invading micro-organisms.
Several studies have pointed out the emergence of immune strategies in mammals in order to fight infection [9, 10]. Moreover, an extensive set of data reveal the dense cross-talk between neuroendocrine and immune systems and supports the evolution of non-immune e.
Among autoimmune disorders, type 1 diabetes and its relations to stress and emotions have been extensively studied. You must be logged in to post a comment Login.Thymopoiesis is essential for development and maintenance of a robust and healthy immune system. Acute thymic atrophy is a complication of many infections, environmental stressors, clinical preparative regimens, and cancer treatments used today.
This undesirable sequela can decrease host ability to reconstitute the peripheral T cell repertoire and respond to new antigens.
Exercise Protects Sympathetic Stress-Induced Myocardial Fibrosis by Regulating Cytokines
Currently, there are no treatments available to protect against acute thymic atrophy or accelerate recovery, thus leaving the immune system compromised during acute stress events. Several useful murine models are available for mechanistic studies of acute thymic atrophy, including a sepsis model of endotoxin-induced thymic involution. We have identified the IL-6 cytokine gene family members i. We have gone on to explore the role of thymosuppressive cytokines and specifically defined a corticosteroid-dependent mechanism of action for the leukemia inhibitory factor in acute thymic atrophy.
We also have identified leptin as a novel, thymostimulatory agent that can protect against endotoxin-induced acute thymic atrophy. This review will highlight mechanisms of stress-induced thymic involution and focus on thymosuppressive agents involved in atrophy induction and thymostimulatory agents that may be exploited for therapeutic use.
The thymus is a specialized, central lymphoid organ located in the thorax above the heart. Postnatally, this bi-lobed organ is composed mostly of thymic epithelial space TESconsisting of developing thymocytes and a supporting stromal thymic epithelial cell network [ 12 ].
Adipocytes, peripheral lymphocytes, and fibroblasts are located in the surrounding perivascular space PVS [ 12 ]. This process, known as thymopoiesis, ensures the establishment of central T cell tolerance in the host [ 345 ]. As these progenitors mature into thymocytes, they provide necessary cross-talk for the further development and maintenance of thymus stroma.
Thymocyte developmental stages can readily be defined by the expression of the cell surface receptors CD4 and CD8. These newly exported T cells are referred to as recent thymic emigrants RTEs [ 8 ]. In humans, monitoring thymus function is typically limited to noninvasive technology, including imaging of thymus size with chest-computed tomography or glucose-analog uptake with positron emission tomography reviewed in Hudson et al.
Given these complications, Douek et al. Douek et al. Acute thymic atrophy can therefore contribute to the development of a less-diverse, oligoclonal peripheral T cell repertoire and constricted host immunity.
In this review, we will discuss mechanisms of stress-induced thymic involution, small animal models used to study mechanisms of stress-induced thymic atrophy, thymosuppressive cytokines that negatively regulate thymopoiesis, and the role of the novel thymostimulatory agent leptin Fig.
Model of stress-induced thymic atrophy and thymosuppressive and thymostimulatory mediators. Stress disrupts the homeostatic balance of the immune system and causes acute thymic involution through physiologic conditions, such as malnutrition, emotional distress, or pregnancy, or pathological conditions, such as infection, disease, clinical cancer treatments, or preparative regimens, for bone marrow transplant.
Stress-induced thymic involution differs from chronic involution. Chronic, age-induced involution is characterized by a gradual expansion of PVS and reduction of TES capable of supporting thymopoiesis, whereas acute thymic involution i. Mechanisms that drive acute thymic involution are poorly understood. Moreover, there are no treatments available to protect against acute thymic atrophy or accelerate recovery, thereby leaving the immune system compromised during acute stress events.
Acute thymic atrophy is a common problem associated with viral, bacterial, and fungal infections [ 15 ]. Unfortunately, HIV-1 infection severely compromises thymus function by the substantial loss of developing thymocytes and thymic stromal cells needed to support thymopoiesis [ 16 ].
Complications from bacterial infections, many times acquired after surgery, result in acute sepsis, which is the 10th leading cause of death in the United States, according to the U. Center for Disease Control [ 17 ]. Sepsis causes massive lymphocyte apoptosis that impairs host T and B cell responses [ 1819 ] and causes severe thymic atrophy [ 14 ]. Critical players in sepsis are glucocorticoids corticosterone in rodents, cortisol in humans induced by activation of the hypothalamus-pituitary-adrenal HPA axis and acute, proinflammatory cytokine cascades [ 20 ].
Acute, stress-induced thymic atrophy is a complication from many environmental stressors as well, in which transient reduction in thymus function persists until the physiological stressor is removed. The effects of malnutrition, starvation, and alcoholism have a negative impact on human thymopoiesis [ 212223 ]. Morphological studies, for example, on autopsy of patients suffering from alcoholism showed decreased size and cellularity of thymus compared with tissue from age-matched nonalcoholics [ 23 ].
Environmental stressors such as prolonged physical or emotional stress can activate the HPA axis to induce production of the stress hormone cortisol, causing abrupt thymus involution and a result in a drop in thymopoiesis [ 24 ]. Additionally, many clinical situations arise in which stress-induced thymic atrophy is a complication of necessary treatment.Cytokines are peptidesand cannot cross the lipid bilayer of cells to enter the cytoplasm.
Cytokines have been shown to be involved in autocrineparacrine and endocrine signaling as immunomodulating agents. Their definite distinction from hormones is still part of ongoing research.
Cytokines include chemokinesinterferonsinterleukinslymphokinesand tumour necrosis factorsbut generally not hormones or growth factors despite some overlap in the terminology. Cytokines are produced by a broad range of cells, including immune cells like macrophagesB lymphocytesT lymphocytes and mast cellsas well as endothelial cellsfibroblastsand various stromal cells ; a given cytokine may be produced by more than one type of cell.
They act through receptorsand are especially important in the immune system ; cytokines modulate the balance between humoral and cell-based immune responses, and they regulate the maturation, growth, and responsiveness of particular cell populations. Some cytokines enhance or inhibit the action of other cytokines in complex ways.
They are different from hormoneswhich are also important cell signaling molecules, in how hormones circulate in higher concentrations and tend to be made by specific kinds of cells. They are important in health and disease, specifically in host responses to infection, immune responses, inflammationtrauma, sepsiscancer, and reproduction. Interferon-alpha, an interferon type Iwas identified in as a protein that interfered with viral replication.
In Dudley Dumonde proposed the term "lymphokine" to describe proteins secreted from lymphocytes and later, proteins derived from macrophages and monocytes in culture were called "monokines". This led to his proposal of the term cytokine. Ogawa described the early acting growth factors, intermediate acting growth factors and late acting growth factors.
Classic hormones circulate in nanomolar 10 -9 M concentrations that usually vary by less than one order of magnitude. In contrast, some cytokines such as IL-6 circulate in picomolar 10 M concentrations that can increase up to 1, times during trauma or infection. The widespread distribution of cellular sources for cytokines may be a feature that differentiates them from hormones. A contributing factor to the difficulty of distinguishing cytokines from hormones is that some immunomodulating effects of cytokines are systemic rather than local.
For instance, to accurately utilize hormone terminology, cytokines may be autocrine or paracrine in nature, and chemotaxischemokinesis and endocrine as a pyrogen. Essentially, cytokines are not limited to their immunomodulatory status as molecules.
Cytokines have been classed as lymphokinesinterleukinsand chemokinesbased on their presumed function, cell of secretion, or target of action. Because cytokines are characterised by considerable redundancy and pleiotropismsuch distinctions, allowing for exceptions, are obsolete. Structural homogeneity has been able to partially distinguish between cytokines that do not demonstrate a considerable degree of redundancy so that they can be classified into four types:.
A key focus of interest has been that cytokines in one of these two sub-sets tend to inhibit the effects of those in the other.
Dysregulation of this tendency is under intensive study for its possible role in the pathogenesis of autoimmune disorders. Several inflammatory cytokines are induced by oxidative stress. Cytokines also play a role in anti-inflammatory pathways and are a possible therapeutic treatment for pathological pain from inflammation or peripheral nerve injury.
In recent years, the cytokine receptors have come to demand the attention of more investigators than cytokines themselves, partly because of their remarkable characteristics, and partly because a deficiency of cytokine receptors has now been directly linked to certain debilitating immunodeficiency states.
In this regard, and also because the redundancy and pleomorphism of cytokines are, in fact, a consequence of their homologous receptors, many authorities think that a classification of cytokine receptors would be more clinically and experimentally useful.
A classification of cytokine receptors based on their three-dimensional structure has, therefore, been attempted. Such a classification, though seemingly cumbersome, provides several unique perspectives for attractive pharmacotherapeutic targets. Each cytokine has a matching cell-surface receptor. Subsequent cascades of intracellular signaling then alter cell functions. The effect of a particular cytokine on a given cell depends on the cytokine, its extracellular abundance, the presence and abundance of the complementary receptor on the cell surface, and downstream signals activated by receptor binding; these last two factors can vary by cell type.
Cytokines are characterized by considerable redundancy, in that many cytokines appear to share similar functions. It seems to be a paradox that cytokines binding to antibodies have a stronger immune effect than the cytokine alone. This may lead to lower therapeutic doses.Regular exercise can improve physical fitness, enhance overall well-being, and may also strengthen the immune system.
Prolonged excessive exercise, however, especially in conjunction with inadequate rest and other stresses, can result in an impairment of athletic performance. This is often associated with a complex of seemingly unrelated physical and psychological symptoms see Table 1a condition known as Overtraining Syndrome OTS. Although overtrained individuals usually exhibit a variable number of the symptoms listed, upper respiratory tract infection is common and may suggest impaired immune function.
A number of hypotheses have been proposed to explain various symptoms associated with OTS, yet none have sufficiently accounted for all the manifestations of the syndrome.
A recent article in Medicine and Science in Sport and Exercise presents an all-encompassing hypothesis focused on the role of cytokines in initiating and perpetuating OTS.
The Cytokine Hypothesis suggests that exercise-induced muscle and connective tissue microtrauma triggers the release of pro-inflammatory cytokines e. The acute inflammation that results from excessive exercise with inadequate rest, however, evolves into a chronic response resulting in a systemic immune response involving the central nervous system CNSliver, and immune system see Figure 1.
CNS function may be influenced by circulating cytokines. IL-1 and IL-6 receptors have been localized to the hypothalamus and thus may modulate both the hypothalamus-pituitary-adrenal HPA axis and the hypothalamus-pituitary-gonadal HPG axis. These systems are regulators of the stress hormones and reproductive hormones, respectively.
Disruption of these systems may thus account for the blunted stress hormone response observed in overtrained athletes, decreased serum testosterone and amenorrhea. Interleukin receptors, especially IL-1 receptors, are also abundant in the hippocampus and therefore may be involved in the impaired cognitive abilities associated with overtraining, such as the inability to concentrate. In addition, the authors suggest that the previously reported correlation between circulating cytokines IL-1, IL-6 and TNF-alpha and depression may also hold for overtraining-induced depression.
Decreased blood glutamine levels have been reported in overtrained individuals and because glutamine is required for lymphocyte proliferation and macrophage function, the decline in this amino acid may contribute to the putative decline in immune function in overtraining. The authors propose that systemic inflammation induces a catabolic state, driven in part by cytokines and glucocorticoids, which mobilize amino acids from skeletal muscle for hepatic gluconeogenesis and synthesis of acute phase proteins.
The detrimental effect of overtraining on immune function may be compared to a model proposed to explain infection susceptibility of patients following surgery and injury.
Following injury, inflammation is upregulated in an attempt to expedite cellular and humoral immune mechanisms. The body attempts to counter this hyper-inflammatory response by producing a multitude of anti-inflammatory molecules.
Systemic exposure to these anti-inflammatory molecules over an extended time period produces a state of immunosuppression, contributing to a high incidence of illness in overtrained athletes. Cytokines are proposed to play a central role in eliciting a large number of the symptoms associated with overtraining. The CNS, liver, and immune system may be responding to a systemic hyper-inflammatory response initiated by trauma to muscular, skeletal, or joint systems.
The Cytokine Hypothesis provides researchers with a framework for further study into the mechanisms responsible for the symptoms of OTS. All Rights Reserved. Skip to main content. Excessive exercise with inadequate rest can result in acute inflammation that evolves into a chronic response. A systemic immune response involves the central nervous system CNSthe liver, and the immune system.Thank you for visiting nature.
Evidence suggests that people who are more responsive to psychological stress are at an increased risk of developing obesity. However, the biological mechanisms underlying this phenomenon are poorly understood. The cytokines leptin, interleukin-1 receptor antagonist IL-1Ra and interleukin-6 IL-6 play a key role in fat metabolism and abnormal circulating levels of these proteins have been reported in obese people and in individuals subject to stress.
This study investigated whether cytokine responses to acute mental stress are associated with adiposity in healthy young women. Height, weight and waist circumference were measured and body fat mass was estimated by bioelectrical impedance body composition analysis.
Saliva samples taken throughout the session were assessed for cortisol. Women who had larger cytokine responses to stress were more abdominally obese than women with smaller cytokine stress responses. Recent years have seen a sharp rise in the prevalence of obesity, with numbers escalating to epidemic proportions in many parts of the world.
Figures in the United Kingdom are similar, with a fourfold increase in the prevalence of obesity in the past quarter century. Women tend to be more prone to obesity than men, and this is particularly evident in developing countries where the prevalence of obesity is 1.
Obvious contributing factors to the rise in obesity are a reduction in levels of physical activity coupled with a rise in consumption of processed, energy-dense food. However, increasing evidence suggests that the stresses of modern day life could also play a significant role.
Psychological stress activates the hypothalamic—pituitary—adrenal HPA axis, resulting in elevations in circulating glucocorticoids, and the sympathetic nervous system SNSleading to increased blood pressure BPheart rate and circulating catecholamines. Waist—hip ratio was associated with heightened stress-related increases in diastolic BP and total peripheral resistance in a study of pre-menopausal women, 12 and waist circumference correlated with greater systolic and diastolic BP and heart rate reactivity to mental stress in older African men and women.
Supporting this, a more recent analysis of middle-aged people from the Whitehall II cohort found that impaired cardiovascular recovery following an acute laboratory stressor, manifest as prolonged elevations in systolic BP and cardiac index, was longitudinally associated with central adiposity in men, predicting a 3-year increase in waist—hip ratio.
Several factors may contribute to individual variation in responsiveness to stress including genetic predisposition, gender, early life and current events.
Despite evidence for a role of the HPA and SNS axes in adiposity, the precise biological mechanisms underlying the association between stress and obesity remain unclear. One potential mechanism might be cytokines. Obesity is associated with a state of chronic systemic low-grade inflammation, and obese humans have elevated circulating levels of a variety of inflammatory markers, including the cytokines leptin, interleukin-1 receptor antagonist IL-1Ra and interleukin-6 IL Evidence from studies in humans suggests that cytokines are sensitive to psychological stress.
Elevated circulating levels of inflammatory cytokines have been reported in people with high levels of perceived daily stress, people of low socioeconomic position and carers of a dementing spouse.
To test this hypothesis, we investigated the relationship between measures of adiposity and cytokine, cardiovascular and neuroendocrine responses to stress in a group of healthy young women. A total of 67 healthy women, aged 18—25 years, were recruited from University College London.
Volunteers were screened by structured interview to ensure that they were healthy, had no previous history of any relevant physical or mental illness, and were not taking any medication.Spinal glia activation has been proposed as one mechanism underlying visceral hyperalgesia in a rodent model of chronic stress.
In order to assess the possible role of changes in circulating cytokines and in blood-spinal cord barrier BSCB permeability in spinal glia activation, we studied the time course of peripheral and spinal pro-inflammatory cytokines and of spinal and satellite glia markers in response to repeated water avoidance stress WA.
Spinal cords and dorsal root ganglion cells DRGs were collected from control rats, rats exposed to 1-hour WA, or 1-hour WA daily for 5 days or 1-hour WA daily for 10 days. These findings confirm the concept that both peripheral and spinal immune makers are altered after chronic WA and suggest a possible link between stress-induced increase of peripheral pro-inflammatory cytokines, changes in satellite glial cells, increased in BSCB permeability and increase in spinal pro-inflammatory mediators suggesting glia activation.
Engagement of the central stress system by acute psychological or physical stressors results in activation of the hypothalamic-pituitary-adrenal HPA axis and the sympathetic nervous system SNSincluding the sympatho-adrenal axis [ 1 ]. The resulting increase in circulating glucocorticoids and catecholamine can influence peripheral immune responses [ 2 ].
Sustained activation of the HPA axis, in association with altered feedback inhibition of the HPA axis response during chronic stress, can lead to disturbance in the balance of pro-inflammatory and anti-inflammatory cytokines. In the CNS, glial cells including microglia and astrocytes, play important roles in immunosurveillance of the microenvironment, monitoring cellular debris, apoptotic cells, alterations in neuronal phenotype and balance of synaptic homeostasis [ 4 ].
While the mechanisms by which stress induces glial secretion of cytokines remain unclear, a role for CNS adrenergic processes has been suggested [ 9 ]. Other studies have suggested that stress does not tonically increase pro-inflammatory cytokines levels but triggers a shift in the pro-inflammatory phenotype of microglia and responsiveness to further immune challenge [ 5 ]. Pro-inflammatory cytokines are important players in both peripheral and central sensitization as demonstrated in a number of experimental studies showing up-regulation of inflammatory cytokines in models of mechanical or thermal hyperalgesia in rats [ 10 - 12 ].
Together, these data suggest a possible interplay between peripheral and CNS inflammatory mediators in the context of chronic pain. In the present study, we propose to assess changes in pro-inflammatory cytokines in a model of stress-induced exacerbated visceral nociception. Using a validated chronic psychological stress model, e. Adult male Wistar rats g Harlan, IN were maintained on a normal light-dark cycle, and provided with food and water ad libitum.
Animals are not directly exposed to the water and when placed on the platform, avoid the aversive stimulus water by remaining on the platform.
Rats were placed on the platform and in case they fell, they were immediately removed from the water, dried, and placed again on the platform. Rats learned quickly to avoid the water and never fell more than one or twice and if so, only during the first exposure to the stressor. The model of chronic water avoidance stress 10 days is a validated model of chronic psychological stress-induced visceral hyperalgesia and has been described in [ 15 ] [ 16 ].
Five groups of rats were studied: one control group in which rats were handled daily. In another group, rats were exposed to a single 1-hour WA session and sacrificed 1 hour later. A third group was exposed to a single WA for 1 hour but sacrificed 24 hours later. A fourth group was exposed to WA for 1 hour on 5 consecutive days and sacrificed 24 hours later.
Finally, a fifth group was exposed to WA for 1 hour on 10 consecutive days and sacrificed 24 hours later. A summary of the experimental groups is provided in figure 1. Blood samples were collected from the trunk and serums were processed for cytokines measurements using standard ELISA. Schematic diagram illustrating the different groups of animals used in the study.
WA: Water avoidance stress. Membranes were stripped and re-blotted with anti-actinCell Signaling. The intensity of immunoreactive bands was quantified using Image Quant software Molecular Dynamics, Sunnyvale, CA and expressed relative to actin.
Spinal cord and DRG samples were collected and homogenized in buffer 0. All samples were run in duplicates and absorbance was measured at nm in a micro plate reader Bio Rad, Model Groups of stressed rats and controls were assigned to FITC-dextran or Evans blue experiments to assess changes in blood-spinal cord barrier permeability:.
The size of FITC-dextran is 4 KDa and its passage into the spinal cord after permeation into the blood is indicative of permeability to small molecules of similar size. Blood spinal cord permeability was determined by Evans Blue extravasation into the spinal cord in separate groups of stressed and control rats. After 45 minutes animals were perfused via a cardiac perfusion with PBS.
Spinal cord tissues were immediately hydroextruded with iced saline and the lumbar spinal cord L6S1 was dissected. Evans blue is known to bind to albumin and its passage into the spinal cord is representative of the passage of molecule of size close to 68KDa and lower. Data were tested for normal distribution using the Kolmogorov-Smirnov normality test and were analyzed using one-way ANOVA followed by Dunnet post-test comparing all groups to the control.As cardiomyocytes of adult mammals have lost significant proliferative capacity, the connective tissue replacement occurs once cardiomyocytes are damaged, thereby inducing the progression of myocardial fibrosis.
When myocardial fibrosis continues to develop, myocardial contractility decreases, coronary flow reserve decreases, thus causing malignant arrhythmia and cardiac death. Early prevention and reversal of myocardial fibrosis is a key to clinical treatment of various heart diseases. However, there is no effective clinical method for treating myocardial fibrosis.Inflammatory Response, Animation
Alemasi et al. Their results showed potential application and mechanisms for treatment of acute sympathetic stress-induced cardiovascular disease with physical exercise. Cytokines are secreted by macrophage. Macrophages are almost always found in the vicinity of myofibroblasts which produce collagen. Macrophages participate in myocardial fibrosis by producing various cytokines such as inflammatory factors, chemokines, and growth factors.
Epac is an upstream molecule of Rap1. Myocardial apoptosis and myocardial fibrosis are reduced in Epac1 knockout mice with ISO-induced chronic stressful heart failure and arrhythmia [ 2 ].
Therefore, inhibition of Rap1 pathway has a very positive significance for prevention and treatment of myocardial fibrosis.
In Alemasi et al. The authors concluded that exercise could improve myocardial fibrosis by inhibiting Rap1 pathway [ 1 ].
Stress-induced cytokine responses and central adiposity in young women
This provides a promising new approach for relieving stress-induced myocardial fibrosis. Chemokines are a group of cytokines with specific reinforcing and attracting functions that can promote myocardial fibrosis mainly by participating in the inflammatory response. The representative chemokine, CCL9, is derived from a variety of cells including mononuclear macrophages, neutrophils, endothelial cells, T lymphocytes, and fibroblasts. These cytokines disrupt calcium homeostasis in myocardial cells through multiple pathways and aggravate myocardial fibrosis.
Long-term exercise can induce cardiomyocyte hypertrophy and promote cardiomyocytes proliferation. MiR overexpression can protect adverse cardiac remodeling and cardiac dysfunction in ischemic injury models [ 4 ]. These cytokines belong to six cytokine families.
Among them, 20 were found significantly upregulated by ISO stimulation; however, running exercise prevented most of these changes induced by ISO. Although the role of RAP1 pathway in cardiac fibrosis has been well-documented, Alemasi et al. On the other hand, Hedgehog pathway has been reported to be critical for kidney injury and fibrosis. However, related studies on the heart have not been reported. Although diseases such as diabetes and myocardial infarction can cause myocardial fibrosis, moderate-intensity continuous exercise and intermittent aerobic exercise can regulate collagen metabolism, correct imbalance of synthesis, and degradation of extracellular matrix, and hence alleviate myocardial fibrosis.
With regard to the mechanism by which exercise protects against myocardial fibrosis, multiple miRNAs have been known involved in the regulation, including miR, miRp, and miR [ 5 ].
New finding today suggests that exercise can also mediate cytokines to protect against myocardial fibrosis [ 1 ]. The search for new molecules and signaling pathways involved in the fibrogenesis process will grow significance in the studies of sports health science.
Alemasi, A. Exercise attenuates acute beta-adrenergic overactivation-induced cardiac fibrosis by modulating cytokines. Journal of cardiovascular and translational research, Jun 3. Cai, W. Disruption of Epac1 protects the heart from adenylyl cyclase type 5-mediated cardiac dysfunction.
Biochemical and Biophysical Research Communications,1—7. Hallab, N. Chemokines associated with pathologic responses to orthopedic implant debris. Frontiers in Endocrinology, 85.
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