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Fibromyalgia (FM) and Chronic Fatigue Syndrome (CFS) are two diseases that are frequently codiagnosed and present many similarities, such as poor tolerance to physical exercise. Although exercise is recommended in their daily routine to improve quality of life, little is known about how CFS codiagnosis affects that. Using scientifically validated questionnaires, we evaluated the psychological state and quality of life of patients with FM (n = 70) and how habitual physical exercise (HPE) reported by patients with only FM (FM-only n = 38) or codiagnosed with CFS (FM + CFS, n = 32) influences those aspects. An age-matched reference group of “healthy” women without FM (RG, n = 70) was used. The FM-only group presented a worse psychological state and quality of life compared to RG, with no influence of CFS codiagnosis. The patients of the FM-only and FM + CFS groups who perform HPE presented better levels of stress and state anxiety, but with no differences between them. Depression and trait anxiety improved only in women with just FM. CFS codiagnosis does not worsen the psychological and quality of life impairment of FM patients and does not have a great influence on the positive effect of HPE.

Although the predominant symptom in fibromyalgia (FM) is muscle pain, and fatigue in chronic fatigue syndrome (CFS), differential diagnosis is very difficult. This research investigates the psychoneuroimmunoendocrine disorders of FM patients and ascertains whether a previous CFS diagnosis affected them. Through accelerometry objective parameters, physical activity/sedentarism levels in relation to fatigue are studied, as well as whether perceived levels of stress, anxiety, and pain correspond to objective biomarkers, all of these with respect to a reference group (RG) of women without FM. FM patients have a worse psychological state and perceived quality of life than those with RG. These perceived outcomes are consistent with impaired objective levels of a sedentary lifestyle, higher systemic levels of cortisol and noradrenaline, and lower levels of serotonin. However, FM patients with a previous CFS diagnosis had lower systemic levels of IL-8, cortisol, oxytocin, and higher levels of adrenaline and serotonin than FM patients without diagnosed CFS. In conclusion, while perceived health parameters do not detect differences, when objective neuroimmunoendocrine parameters related to stress, inflammation, pain, and fatigue are used, people with CFS could be overdiagnosed with FM. This reinforces the need for objective biomarker assessment of these patients for better diagnostic discrimination between both syndromes.

Fibromyalgia (FM) and chronic fatigue syndrome (CFS) are two medical conditions in which pain, fatigue, immune/inflammatory dysregulation, as well as various mental health disorders predominate in the diagnosis, without evidence of a clear consensus on the treatment of FM and CFS. The main aim of this research was to analyse the possible effects of a synbiotic (Synbiotic, Gasteel Plus® (Heel España S.A.U.), through the study of pro-inflammatory/anti-inflammatory cytokines (IL-8/IL-10) and neuroendocrine biomarkers (cortisol and DHEA), in order to evaluate the interaction between inflammatory and stress responses mediated by the cytokine-HPA (hypothalamic-pituitary-adrenal) axis, as well as mental and physical health using body composition analysis, accelerometry and previously validated questionnaires. The participants were women diagnosed with FM with or without a diagnostic of CFS. Each participant was evaluated at baseline and after the intervention, which lasted one month. Synbiotic intervention decreased levels of perceived stress, anxiety and depression, as well as improved quality of life during daily activities. In addition, the synbiotic generated an activation of HPA axis (physiological cortisol release) that can compensate the increased inflammatory status (elevated IL-8) observed at baseline in FM patients. There were no detrimental changes in body composition or sleep parameters, as well as in the most of the activity/sedentarism-related parameters studied by accelerometry. It is concluded that synbiotic nutritional supplements can improve the dysregulated immunoneuroendocrine interaction involving inflammatory and stress responses in women diagnosed with FM, particularly in those without a previous CFS diagnostic; as well as their perceived of levels stress, anxiety, depression and quality of life.

Obesity is characterized by low-grade inflammation and more susceptibility to infection, particularly viral infections, as clearly demonstrated in COVID-19. In this context, immunometabolism and metabolic flexibility of macrophages play an important role. Since inflammation is an inherent part of the innate response, strategies for decreasing the inflammatory response must avoid immunocompromise the innate defenses against pathogen challenges. The concept “bioregulation of inflammatory/innate responses” was coined in the context of the effects of exercise on these responses, implying a reduction in excessive inflammatory response, together with the preservation or stimulation of the innate response, with good transitions between pro- and anti-inflammatory macrophages adapted to each individual’s inflammatory set-point in inflammatory diseases, particularly in obesity. The question now is whether these responses can be obtained in the context of weight loss by dietary interventions (low-fat diet or abandonment of the high-fat diet) in the absence of exercise, which can be especially relevant for obese individuals with difficulties exercising such as those suffering from persistent COVID-19. Results from recent studies are controversial and do not point to a clear anti-inflammatory effect of these dietary interventions, particularly in the adipose tissue. Further research focusing on the innate response is also necessary.

Obesity is a chronic condition associated with low-grade inflammation, and it also involves alterations of the function of the hypothalamic-pituitaryadrenal axis and the sympathetic nervous system. Adrenergic agonists such as catecholamines are important immunoregulatory molecules that are involved in modulating both metabolism and most of the mechanisms of the immune response. The first objective of this study was to determine whether the systemic inflammatory state associated with obesity is also manifested in the inflammatory profile and phenotype of circulating monocytes; and the second objective was to evaluate the effects of β2 adrenergic stimulation on the inflammatory profile and phenotype of monocytes in obesity, and whether this response could be different from that in lean individuals. C57BL/6J mice were randomly allocated to one of two diets for 18 weeks: high-fat diet in order to obtain an experimental model of obesity, and standard diet in the control lean group. Circulating monocyte expression of inflammatory cytokines (MCP-1, TNF-α, IL-8, IL-6, IL-10, and TGF-β), surface membrane marker Ly6C, inducible nitric oxide synthase and arginase-1, and Toll-like receptor 4 were evaluated through flow cytometry in the presence or absence of selective β2 adrenergic receptor agonist terbutaline. Monocytes from high-fat diet-induced obese animals presented higher expression levels of all pro-inflammatory cytokines and a higher percentage of monocytes with a pro-inflammatory phenotype than those from lean animals. β2 adrenergic stimulation induced a shift towards an anti-inflammatory activity profile and phenotype in obese mice, whereas it induced a shift towards a pro-inflammatory activity profile and phenotype in lean mice. In conclusion, β2 adrenergic stimulation in monocytes was anti-inflammatory only in obese animals, which presented a pro-inflammatory state at baseline.

The main objective of this research was to carry out an experimental study, triple-blind, on the possible immunophysiological effects of a nutritional supplement (synbiotic, Gasteel Plus®, Heel España S.A.U.), containing a mixture of probiotic strains, such as Bifidobacterium lactis CBP-001010, Lactobacillus rhamnosus CNCM I-4036, and Bifidobacterium longum ES1, as well as the prebiotic fructooligosaccharides, on both professional athletes and sedentary people. The effects on some inflammatory/immune (IL-1β, IL-10, and immunoglobulin A) and stress (epinephrine, norepinephrine, dopamine, serotonin, corticotropin-releasing hormone (CRH), Adrenocorticotropic hormone (ACTH), and cortisol) biomarkers were evaluated, determined by flow cytometer and ELISA. The effects on metabolic profile and physical activity, as well as on various parameters that could affect physical and mental health, were also evaluated via the use of accelerometry and validated questionnaires. The participants were professional soccer players in the Second Division B of the Spanish League and sedentary students of the same sex and age range. Both study groups were randomly divided into two groups: a control group—administered with placebo, and an experimental group—administered with the synbiotic. Each participant was evaluated at baseline, as well as after the intervention, which lasted one month. Only in the athlete group did the synbiotic intervention clearly improve objective physical activity and sleep quality, as well as perceived general health, stress, and anxiety levels. Furthermore, the synbiotic induced an immunophysiological bioregulatory effect, depending on the basal situation of each experimental group, particularly in the systemic levels of IL-1β (increased significantly only in the sedentary group), CRH (decreased significantly only in the sedentary group), and dopamine (increased significantly only in the athlete group). There were no significant differences between groups in the levels of immunoglobulin A or in the metabolic profile as a result of the intervention. It is concluded that synbiotic nutritional supplements can improve anxiety, stress, and sleep quality, particularly in sportspeople, which appears to be linked to an improved immuno-neuroendocrine response in which IL-1β, CRH, and dopamine are clearly involved.

Background: Hypercholesterolemia is one of the principal causes of the development of cardiovascular diseases. Recently, probiotics consumption has also been proposed as a non-pharmacological intervention to control cholesterol concentrations. Objective: To evaluate in vitro assimilation of cholesterol by Bifidobacterium animalis subsp. lactis (BPL1) under simulated intestinal environment in anaerobic conditions and to review and discuss potential physiological mechanisms in this context. Methods: Bacterial viability and cholesterol assimilation were evaluated in both standard MRS and Stimulated Intestinal Fluid (SIF) medium under anaerobic conditions and in the presence or absence of cholesterol. For assimilation assays, cholesterol concentrations in the different suspensions, containing the probiotic or not, were determined by chromatography coupled to mass spectrometry. Results: The results showed that the growth of B. lactis BPL1 under intestinal conditions is favored when cholesterol is present in the culture medium. In addition, cholesterol assimilation of up to 44.4% under intestinal and anaerobic conditions was observed. Conclusion: Taking into account the revised literature and the experimental results presented herein, the administration of functional foodstuffs together with probiotic bacteria, such as B. lactis BPL1, could be a potentially effective option to decrease hypercholesterolemia, thus preventing the development of cardiovascular diseases. Nevertheless, further studies on mechanisms of effectiveness in animals and clinical trials are still needed.

The purpose of the present investigation was to evaluate whether an anti-inflammatory effect together with an improvement of the regulation of the interaction between the inflammatory and stress responses underlies the clinical benefits of pelotherapy in osteoarthritis (OA) patients. This study evaluated the effects of a 10-day cycle of pelotherapy at the spa centre 'El Raposo' (Spain) in a group of 21 OA patients diagnosed with primary knee OA. Clinical assessments included pain intensity using a visual analog scale; pain, stiffness and physical function using the Western Ontario and McMaster Universities Arthritis Index; and health-related quality of life using the EuroQol-5D questionnaire. Serum inflammatory cytokine levels (IL-1β, TNF-α, IL-8, IL-6, IL-10 and TGF-β) were evaluated using the Bio-Plex® Luminex® system. Circulating neuroendocrine-stress biomarkers, such as cortisol and extracellular 72 kDa heat shock protein (eHsp72), were measured by ELISA. After the cycle of mud therapy, OA patients improved the knee flexion angle and OA-related pain, stiffness and physical function, and they reported a better health-related quality of life. Serum concentrations of IL-1β, TNF-α, IL-8, IL-6 and TGF-β, as well as eHsp72, were markedly decreased. Besides, systemic levels of cortisol increased significantly. These results confirm that the clinical benefits of mud therapy may well be mediated, at least in part, by its systemic anti-inflammatory effects and neuroendocrine-immune regulation in OA patients. Thus, mud therapy could be an effective alternative treatment in the management of OA.

Anomalous immune/inflammatory responses in obesity take place along with alterations in the neuroendocrine responses and dysregulation in the immune/stress feedback mechanisms. Exercise is a potential anti-inflammatory strategy in this context, but the influence of exercise on the &beta, 2 adrenergic regulation of the monocyte-mediated inflammatory response in obesity remains completely unknown. The first objective of this study was to analyze the effect of exercise on the inflammatory profile and phenotype of monocytes from obese and lean animals, and the second aim was to determine whether obesity could affect monocytes&rsquo, inflammatory response to &beta, 2 adrenergic activation in exercised animals. C57BL/6J mice were allocated to different lean or obese groups: sedentary, with acute exercise, or with regular exercise. The inflammatory profile and phenotype of their circulating monocytes were evaluated by flow cytometry in the presence or absence of the selective &beta, 2 adrenergic receptor agonist terbutaline. Exercise caused an anti-inflammatory effect in obese individuals and a pro-inflammatory effect in lean individuals. &beta, 2 adrenergic receptor stimulation exerted a global pro-inflammatory effect in monocytes from exercised obese animals and an anti-inflammatory effect in monocytes from exercised lean animals. Thus, &beta, 2 adrenergic regulation of inflammation in monocytes from exercised animals seems to depend on the inflammatory basal set-point.

Obese individuals present anomalous immune/inflammatory responses with dysregulations in neuroendocrine responses and immune/stress feedback mechanisms. In this context, exercise and &beta, 2 adrenergic activation present monocyte-mediated anti-inflammatory effects that are modulated by obesity. However, these anti-inflammatory effects could immunocompromise the monocyte-mediated innate response against a pathogen challenge. Thus, the objective of this work was to evaluate the effect of obesity, and exercise in this condition, on the &beta, 2 adrenergic regulation of the phagocytic and microbicide capacity of circulating monocytes. C57BL/6J mice were allocated to different sedentary or exercised, lean or obese groups. Obese mice showed a lower monocyte-mediated innate response than that of lean mice. Globally, selective &beta, 2 adrenergic receptor agonist terbutaline decreased the innate response of monocytes from lean and obese sedentary animals, whereas exercise stimulated it. Exercise modulates &beta, 2 adrenergic regulation of the innate response in lean and obese animals, with a global stimulatory or neutral effect, thus abolishing the inhibitory effect of terbutaline occurring in sedentary animals. These effects cannot be explained only by changes in the surface expression of toll-like receptors. Therefore, in general, terbutaline does not hinder the effects of regular exercise, but regular exercise does abolish the effects of terbutaline in sedentary individuals.

Macrophages are crucial in the inflammation associated with obesity. Exercise is the main non-pharmacological strategy against obesity, not only for improving metabolic impairment, but also because of its anti-inflammatory effects, particularly those mediated by &beta, 2 adrenergic receptors (&beta, 2-AR). Nevertheless, these anti-inflammatory effects could immunocompromise the innate response against pathogen challenge. Thus, the objective of this work was to evaluate the effect of obesity, and of exercise in this condition, on the &beta, 2 adrenergic regulation of the innate function of macrophages. High fat diet-induced obese C57BL/6J mice were used to evaluate the effects of acute and regular exercise on the phagocytic and microbicide capacities of peritoneal macrophages. Selective &beta, 2-AR agonist terbutaline (1 &micro, M) decreased the phagocytic and microbicide activities of macrophages from control lean and obese sedentary animals. While acute exercise did not modify the inhibitory capacity of terbutaline, regular exercise abolished this inhibitory effect. These effects cannot be explained only by changes in the surface expression of &beta, 2-AR. In conclusion, (1) obesity does not alter the &beta, 2-AR-mediated decrease of the innate response of macrophages and (2) regular exercise can revert the inhibitory effect of terbutaline on the phagocytic activity of macrophages, although obesity seems to hinder this immunophysiological adaptation.

Aunque se ha demostrado que la balneoterapia con agua mineromedicinales(bicarbonatadas calcicas) y peloides (limos y arcillas) produce beneficios clinicos en pacientes con osteoartritis (OA) (Espejo-Antunez y cols., 2013), aun se desconocen los mecanismos inmunofisiologicos a traves de los cuales se pueden ejercer dichos efectos; aspecto de gran importancia para validar estas estrategias como ayudas terapeuticas en la OA dentro del ambito sanitario. En estudios previos muy recientes realizados por nuestro grupo de investigacion (presentados tambien en el presente congreso) se han corroborado los beneficios clinicos tras un ciclo de 10 sesiones diarias de balneoterapia con peloides (pincelacion del peloide, bano con agua mineromedicinal y peloide, y chorro a baja presion de agua mineromedicinal), independientemente de que los peloides estuviesen madurados de forma controlada o de forma natural en arroyo procedente de manantial de agua mineromedicinal (Balneario “El Raposo”, Puebla de Sancho Perez, Badajoz, Espana). Teniendo esto en cuenta, el objetivo de la presente investigacion ha sido doble: 1) Por un lado evaluar un potencial efecto anti-inflamatorio mediado por IL-1β y cortisol de esta estrategia balneoterapeutica con peloides en pacientes con OA. 2) Por otro lado determinar la caracteristicas de no inferioridad en los efectos evalua dos entre el peloide madurado de forma controlada en relacion al madurado de forma natural. Para llevar a cabo este estudio, prospectivo triple ciego, se determinaron los niveles sericos de IL-1β y cortisol (a traves de la tecnica “Bioplex-Luminex®” y ELISA, respectivamente) en 21 pacientes con OA tanto en situacion basal como post-tratamiento; siendoles aplicado a 11 de ellos el peloide madurado de forma natural y a los 10 restantes el madurado de forma controlada. Los resultados muestran claramente que tras el ciclo con balneoterapia los pacientes con OA disminuyeron significativamente sus niveles de IL-1β y aumentaron los de cortisol, si bien en este ultimo caso no se observaron variaciones significativas con la aplicacion del peloide madurado de forma controlada. En cualquier caso, el estudio estadistico refleja una respuesta de no inferioridad del “peloide controlado” respecto al “peloide natural”, ya que no existen diferencias significativas en cuanto al comportamiento entre ambos, ni en el analisis de los niveles de IL-1β ni en el de cortisol (Figura 1). Se puede concluir por tanto, que la balneoterapia aplicada en el balneario “El Raposo” con aguas mineromedicinales bicarbonatadas calcicas y peloides (de limo y arcilla) induce un efecto anti-inflamatorio que subyace a los beneficios clinicos que se obtienen en pacientes con OA con esta estrategia. Ademas, este efecto se produce, en general, independientemente de la tecnica de maduracion del peloide que se aplica.

Background Fibromyalgia (FM) is a syndrome characterized by widespread chronic pain. Its aetiology is still poorly understood, and there are no haematochemical or instrumental tests on which to base a diagnosis. Recent studies suggest that its pathogenesis may involve cytokines, in particular, chemokines – cytokines that regulate cell traffic under both physiological and pathological conditions. The aim of this study was to determine possible differences in the profile of systemic concentrations of chemokines between FM patients and healthy women (HW; controls). Methods The study participants were women diagnosed with FM ( n = 17) and a control group of HW ( n = 10). Serum concentrations of thymus and activation-regulated chemokine (TARC)/(CCL17), monokine induced by gamma-interferon (MIG)/(CXCL9), macrophage-derived chemokine (MDC)/(CCL22), interferon-inducible T-cell alpha chemoattractant (I-TAC)/(CXCL11), eotaxin (CCL11), pulmonary and activation-regulated chemokine (PARC)/(CCL18) and hemofiltrate CC-chemokine-4 (HCC-4)/(CCL16) were determined by enzyme-linked immunosorbent assay and compared between the FM and HW groups. Results FM patients had elevated serum levels of the following inflammatory chemokines: TARC ( P Conclusions Since FM patients present higher serum concentrations of inflammatory chemokines than HW, the evaluation of these biomarkers could help in the diagnosis of this syndrome.

Background Although osteoarthritis (OA) has predominantly been considered a noninflammatory degenerative arthropathy, there is growing evidence that various inflammatory and immunological processes might contribute to the onset, progression, and burden of the disease. Objective The purpose of the present investigation was to study the systemic inflammatory and stress responses and the innate response mediated by neutrophils in OA patients. Method A group of patients diagnosed with primary OA according to the American College of Rheumatology criteria and a control group of age-matched healthy volunteers were enrolled in the study. Serum inflammatory cytokine levels (IL-1β, TNF-α, IL-8, IL-6, IL-10, and TGF-β) were evaluated using the Bio-Plex Luminex system. Circulating neuroendocrine-stress biomarkers, such as cortisol and extracellular 72 kDa heat shock protein (eHsp72), were measured by ELISA. The phagocytic and microbicide capacities of circulating neutrophils were evaluated by flow cytometry. All parameters were determined in all volunteers. Results The OA patients showed an inflammatory state accompanied by an altered stress response. This was manifested in high circulating levels of the inflammatory cytokines IL-1β, TNF-α, IL-8, IL-6, and TGF-β and the stress protein eHsp72. There were also decreased systemic levels of cortisol, and a reduction in neutrophil phagocytic and microbicidal capacities. Conclusion An immune-neuroendocrine dysregulation affecting both systemic inflammatory and stress mediators and the function of innate immune cells underlies OA. This reflects an altered feedback between the innate/inflammatory and stress responses in this pathology.

Regular exercise is a good non-pharmacological treatment of metabolic syndrome in that it improves obesity, diabetes, and inflammation. The 72 kDa extracellular heat shock protein (eHsp72) is released during exercise, thus stimulating the inflammatory responses. The aim of the present work was to evaluate the effect of regular exercise on the eHsp72-induced release of IL-1β, IL-6, and TNFα by macrophages from genetically obese Zucker rats ( fa/fa ) (ObZ), using lean Zucker (LZ) rats ( Fa/fa ) to provide reference values. ObZ presented a higher plasma concentration of eHsp72 than LZ, and exercise increased that concentration. In response to eHsp72, the macrophages from ObZ released less IL-1β and TNFα, but more IL-6, than macrophages from LZ. While eHsp72 stimulated the release of IL-1β, TNFα, and IL-6 in the macrophages from healthy LZ (with respect to the constitutive release), it inhibited the release of IL-1β and IL-6 in macrophages from ObZ. The habitual exercise improved the release of inflammatory cytokines by macrophages from ObZ in response to eHsp72 (it increased IL-1β and TNFα, and decreased IL-6), tending to values closer to those determined in healthy LZ. A deregulated macrophage inflammatory and stress response induced by eHsp72 underlies MS, and this is improved by habitual exercise.

Objectives: The first objective was to evaluate whether the metabolic syndrome (MS) involves deregulation of TNF-α and IL-6 release by non-infiltrated peritoneal macrophages, using obese Zucker rats as the experimental model of MS and lean Zucker rats as a reference for healthy control values. The second purpose was to evaluate in the obese rats the effects of habitual exercise and of a bout of acute exercise on the observed MS-associated deregulation in the release of TNF-α and IL-6 by peritoneal macrophages. Methods: The habitual exercise consisted of treadmill running: 5 days/week for 14 weeks and 35 cm/s for 35 min in the last month. The acute exercise consisted of a single session of 25–35 min at 35 cm/s. The constitutive or lipopolysaccharide (LPS)-induced release of TNF-α and IL-6 by cultured (24 h, 5% CO2, 100% relative humidity) peritoneal macrophages was determined by ELISA. Results: Macrophages from the obese rats released more IL-6 than those from the lean healthy rats, both spontaneously and after LPS stimulation. However, both spontaneous and LPS-induced release of TNF-α was lower in the obese rats. This deregulated balance in the release of IL-6 and TNF-α in the obese rats was clearly improved following adherence to the program of habitual exercise, reflected by a decrease in the spontaneous release of IL-6 together with a better regulation between the spontaneous and LPS-induced release of TNF-α, approaching the behavior of the lean healthy rats. In addition, an acute bout of exercise decreased the spontaneous release of IL-6 and increased the spontaneous release of TNF-α in the sedentary, but not in the exercise-adapted obese rats. Conclusion: MS involves a deregulation of TNF-α and IL-6 release by non-infiltrated peritoneal macrophages, which is improved by habitual physical activity.

In humans, Candida albicans is the microorganism most frequently associated with fungal infections. Alterations in the balance between the host and this commensal pathogen, turns into a parasitic relationship which results in the development of invasive infections. Neutrophils via chemotaxis, phagocytosis, and microbicide capacity can eradicate this pathogen. Taken together, the aim of this work was to study the possible role of phosphatidylinositol-3-kinase (PI3K), extracellular signal-regulated kinase (ERK) and the nuclear transcription factor kappa beta (NF-k beta) on the phagocytic process of neutrophils. The chemotactic capacity of neutrophils and their ability to phagocytose and to destroy C. albicans in absence and presence of 1, 10, or 100 microM of wortmannin (a PI3K inhibitor); 10, 25, or 50 microM of Bay 11-7082 (a NF-k beta inhibitor) or 1, 5 or 10 microM of PD 98,059 (an ERK inhibitor) were determined. Our results show that fMLP-induced chemotaxis needs the participation of PI3K and NF-k beta. In contrast, ERK seems not to be involved. On the other hand, the inhibition of NF-kappa beta and ERK decreased neutrophil phagocytosis and microbicide capacity against C. albicans. However, both the phagocytic and candicide capacities were PI3K independent.

The purpose of the present work was to determine differences between young men (M), and women in the follicular phase (W) and women taking oral contraceptives containing ethinylestradiol (CW) in the phagocytic process of neutrophils (chemotaxis, phagocytosis and microbicide capacity), in the serum concentrations of cytokines both pro-inflammatory (IFNgamma, TNFalpha, IL-12, IL-6, IL-8) and anti-inflammatory ones (IL-10 and IL-13), and in neuroendocrine factors with immunomodulatory capacity (estradiol, prolactin, cortisol, catecolamines and 72 kDa heat shock proteins, Hsp72). Men showed a lower phagocytosis and microbicide capacity than women, and less serum concentrations of the pro-inflammatory cytokines IL-6 and IL-8. CW neutrophils also showed a lower phagocytic capacity than W neutrophils, together with less serum IL-8 concentration. CW showed the highest serum concentration of IL-13. However, no statistical changes were observed in the pro-inflammatory cytokines: INF-gamma, TNF-alpha, IL-12 and in the anti-inflammatory cytokine IL-10. The greater anti-inflammatory status in CW than in W was parallel with lower concentrations of oestrogens. Cortisol, prolactin, and the extracellular Hsp72 seem to be involved in the gender- and contraceptives-induced differences in the inflammatory response. While cortisol (in general an immunosuppressive hormone) showed the highest values in CW, prolactin and Hsp72 (an immunopermissive factors) showed the lowest values in CW and M. Less clear is the participation of catecholamines in the gender-inflammatory differences.

Fibromyalgia (FM) syndrome is associated with elevated systemic inflammatory and stress biomarkers, and an elevated innate cellular response mediated by monocytes and neutrophils. Exercise is accepted as a good non-pharmacological therapy for FM. We have previously found that regular aquatic exercise decreases the release of inflammatory cytokines by monocytes from FM patients. However, its effects on the functional capacity of neutrophils have not been studied. The aim of the present exploratory study was to evaluate, in 10 women diagnosed with FM, the effect of an aquatic exercise program (8months, 2sessions/week, 60min/session) on their neutrophils' function (phagocytic process), and on IL-8 and NA as potential inflammatory and stress mediators, respectively. A control group of 10 inactive FM patients was included in the study. After 4months of the exercise program, no significant changes were observed in neutrophil function (chemotaxis, phagocytosis, or fungicidal capacity) or in IL-8 and NA. However, at the end of the exercise program (8months), a neuro-immuno-endocrine adaptation was observed, manifested by a significant decrease to values below those in the basal state in neutrophil chemotaxis, IL-8, and NA. No significant seasonal changes in these parameters were observed during the same period in the group of non-exercised FM patients. After the 8months of the exercise program, the FM patients had lower concentrations of IL-8 and NA together with reduced chemotaxis of neutrophils compared with the values determined in the same month in the control group of non-exercised FM women. These results suggest that "anti-inflammatory" and "anti-stress" adaptations may be contributing to the symptomatic benefits that have been attributed to regular aquatic exercise in FM syndrome, as was corroborated in the present study by the scores on the Fibromyalgia Impact Questionnaire.

Extracellular heat shock proteins of 72 kDa (eHsp72) and noradrenaline (NA) can act as “danger signals” during exercise-induced stress by activating neutrophil function (chemotaxis, phagocytosis, and fungicidal capacity). In addition, post-exercise concentrations of NA increase the expression and release of Hsp72 by human neutrophils, and adrenoreceptors and cAMP are involved in the stimulation of neutrophils by eHsp72. This suggests an interaction between the two molecules in the modulation of neutrophils during exercise-induced stress. Given this context, the aim of the present investigation was to study the combined activity of post-exercise circulating concentrations of NA and eHsp72 on the neutrophil phagocytic process, and to evaluate the role of cAMP as intracellular signal in these effects. Results showed an accumulative stimulation of chemotaxis induced by NA and eHsp72. However, while NA and eHsp72, separately, stimulate the phagocytosis and fungicidal activity of neutrophils, when they act together they do not modify these capacities of neutrophils. Similarly, post-exercise concentrations of NA and eHsp72 separately increased the intracellular level of cAMP, but NA and eHsp72 acting together did not modify the intracellular concentration of cAMP. These results confirm that cAMP can be involved in the autocrine/paracrine physiological regulation of phagocytosis and fungicidal capacity of human neutrophils mediated by NA and eHsp72 in the context of exercise-induced stress. J. Cell. Physiol. 228: 1902–1906, 2013. © 2013 Wiley Periodicals, Inc.

Objective: Although one of the current hypotheses of the aetiology of fibromyalgia (FM) syndrome involves inflammatory and neuroendocrine disorders, its biophysiology still remains unclear. The purpose of the present investigation was to study the systemic inflammatory and stress responses, as well as the innate response mediated by monocytes and neutrophils in FM patients. Methods: Twenty-five women diagnosed with primary FM and 20 age-matched healthy women (control group) were enrolled in the study. Circulating ‘neuroendocrine-stress’ biomarkers (CRH, ACTH, cortisol, NA, eHsp72, serotonin and IGF-1) were evaluated by ELISA. Serum IL-8 and CRP concentrations were also determined by ELISA, and inflammatory cytokine release by monocytes [IL-1β, TNFα, IL-6, IL-10, IL-18, monocyte chemotactic protein-1 (MCP-1) and RANTES] was evaluated by the Luminex BioPlex system. The phagocytic process of neutrophils (chemotaxis, phagocytosis and microbicide capacity) was also evaluated. Results: FM patients showed an inflammatory state accompanied by an altered stress response. This is mainly manifested by high circulating levels of IL-8 and CRP (in 100% of the FM group), high circulating levels of cortisol, and increased systemic levels of NA and eHsp72. There is also increased release of inflammatory cytokines (IL-1β, TNFα, IL-6, IL-10, IL-18 and MCP-1) by monocytes, and enhanced activation of the functional capacity of neutrophils (chemotactic, phagocytic and fungicidal activities). Conclusion: An inflammatory/stress feedback dysregulation underlies FM. Whether dysregulation of the stress response is the cause of the inflammatory dysregulation or vice versa is also discussed.

Regular physical exercise is recognized as a nonpharmacological therapeutic strategy in the treatment of metabolic syndrome, and has been proposed for improving obesity, diabetic status, insulin resistance, and immune response. The aim of the present study was to evaluate the effect of a regular exercise program (treadmill running, 5 days/week for 14 weeks at 35 cm/s for 35 min in the last month) on the release of the pro-inflammatory cytokine interferon gamma (IFNγ) by peritoneal cells (macrophages and lymphocytes) from obese Zucker rats (fa/fa) in response to noradrenaline (NA) and heat shock proteins of 72 kDa (Hsp72), and the possible adaptation due to training for a bout acute exercise (a single session of 25–35 min at 35 cm/s). In healthy (lean Fa/fa) and obese animals, peritoneal cells released greater concentrations of IFNγ in response to Hsp72 and lower concentrations in response to NA. The regular exercise training protocol, evaluated in the obese animals, produced a clear change in the regulation of the release of IFNγ. Peritoneal immune cells from trained animals released more IFNγ in response to NA, but there was a reduction in the release of IFNγ in response to Hsp72. In the obese animals, regular exercise caused a change in the inhibitory effect of NA (which now becomes stimulatory) and the stimulatory effect of Hsp72e (which now becomes inhibitory) in relation to the release of IFNγ. This reflects that Hsp72, induced by the prior release of NA following exercise-induced stress, plays a role in the homeostatic balance of release of IFNγ by peritoneal immune cells in obese animals during exercise.

Recently, the terms "stress mediators" or "danger signals" have come to be used to describe endogenous molecules that can be released in stress situations and activate the innate immune system even in the absence of antigenic stimuli. There is evidence suggesting that extracellular heat shock proteins of 72 kDa (eHsp72), together with noradrenaline (NA), are candidates as danger signals during exercise-induced stress, interacting in the activation of neutrophils. Previous studies have shown that the post-exercise circulating concentration of eHsp72 activates the phagocytic process of neutrophils with the participation of toll-like receptor 2, but that other receptors must also be involved. The present investigation evaluates the role of adrenoreceptors in the activation of the chemotaxis, phagocytosis, and fungicidal capacity of neutrophils by the post-exercise circulating concentration of eHsp72. The results showed that intact α- and β-adrenoreceptors are necessary for the stimulation of all stages of the phagocytic process by eHsp72. Also, eHsp72 increased the intracellular levels of cAMP, suggesting that it is an "intracellular danger signal" during stress-induced activation of neutrophils mediated by extracellular heat shock proteins. These results can contribute to better understanding the mechanisms involved in the regulation of the innate immune response mediated by "danger signals" during exercise, and probably during other stress situations.

Physical activity has a great capacity for modulating the immune system, including the inflammatory response. However, the effects of exercise on the inflammatory response have rarely been studied in women, even though women are more susceptible than men to chronic inflammatory diseases. The aim of this study was to ascertain the effect of single sessions of exercise on the inflammatory response of sedentary women, evaluating neutrophil function and circulating concentrations of inflammatory cytokines. Exercise consisted of one session of cycling (1 h at ~70% of VO2 max) on a cycle ergometer. Blood samples were taken in the basal state and immediately after the exercise session. Neutrophil function was studied on isolated cells by evaluating their phagocytic capacity against latex beads and their oxygen-dependent microbicidal capacity as reflected in the superoxide anion (O2 −) production. Circulating inflammatory cytokines were determined using a novel antibody-based protein micro-array method. The circulating concentration of IL-8 (a stimulatory cytokine for neutrophils) was also determined by ELISA. Exercise increased the phagocytic and the oxygen-dependent microbicidal capacities of neutrophils in the sedentary women. No variations were found in IL-2, IL-3, IL-5, IL-6, IL-7, IL-8, IL-10, IL-13, IFN-γ, TNF-α and -β, TGF-β, MCP-2 and -3, MIG, G-CSF, and GM-CSF. However, while the circulating concentrations of GRO and MCP-1 increased after exercise, there was a decrease in that of RANTES, a pro-inflammatory cytokine. Exercise improves neutrophil function, possibly mediated, at least partially, by GRO (a potent neutrophil activator) but not by IL-8. This stimulation of neutrophil function does not seem to be accompanied by any harmful systemic inflammatory response since no changes in the main pro-inflammatory cytokines were observed, and there was a decrease in RANTES.

We studied the physiological role of the 72 kDa extracellular heat shock protein (Hsp72, a stress-inducible protein) in modulating neutrophil chemotaxis during a single bout of intense exercise performed by sedentary women, together with various cell mechanisms potentially involved in the modulation. For each volunteer, we evaluated neutrophil chemotaxis and serum Hsp72 concentration before and immediately after a single bout of exercise (1 h on a cycle ergometer at 70% VO(2) max), and 24 h later. Both parameters were found to be stimulated by the exercise, and had returned to basal values 24 h later. In vitro, there was a dose-dependent increase in chemotaxis when neutrophils were incubated both with physiological Hsp72 concentrations and with a 100 x greater concentration. The chemotaxis was greater when the neutrophils were incubated with the post-exercise Hsp72 concentration than with the basal concentration, suggesting a physiological role for this protein in the context of the stimulation of neutrophil chemotaxis by intense exercise. The 100 x Hsp72 concentration stimulated chemotaxis even more strongly. In addition, Hsp72 was found to have chemoattractant and chemokinetic effects on the neutrophils at physiological concentrations, with these effects being significantly greater with the post-exercise than with the basal Hsp72 concentration. The Hsp72-induced stimulation of neutrophil chemotaxis disappeared when the toll-like receptor 2 (TLR-2) was blocked, and phosphatidylinositol-3-kinase (PI3K), extracellular signal-regulated kinase (ERK), and nuclear transcription factor kappa B (NF-kappaB) were also found to be involved in the signaling process. No changes were observed, however, in neutrophil intracellular calcium levels in response to Hsp72. In conclusion, physiological concentrations of the stress protein Hsp72 stimulate human neutrophil chemotaxis through TLR-2 with its cofactor CD14, involving ERK, NF-kappaB, and PI3K, but not iCa(2 + ), as intracellular messengers. In addition, Hsp72 seems to participate in the stimulation of chemotaxis induced by a single bout of intense exercise performed by sedentary women.

Background: It is still not really known what is the optimal level of exercise that improves, but does not impair or overstimulate the innate immune function. This is especially the case in women, who have higher basal levels of ‘inflammatory markers’ than men. The aim of this work was to evaluate differences in the magnitude of the stimulation of the innate/inflammatory response following a single bout of moderate or intense exercise in sedentary women, all of them in the follicular phase of their menstrual cycle. Changes in stress and sexual hormones were also evaluated. Methods: Changes induced by exercise (45 min at 55% VO2 max vs. 1 h at 70% VO2 max on a cycle ergometer) in the phagocytic process (chemotaxis, phagocytosis, and microbicide capacity against Candida albicans) and in serum concentrations of IL-1β, IL-2, IFN-γ, IL-12, IL-6, and IL-4 (ELISA) were evaluated. Parallel determinations were also made of serum or plasma concentrations of catecholamines (HPLC) and cortisol, oestradiol, and progesterone (electrochemiluminescence immunoassay). Results: Both exercise intensities increased chemotaxis, phagocytosis, and microbicide capacity of the neutrophils. However, the increase in chemotaxis was greater after moderate exercise. All the cytokines assayed were affected by exercise intensity. IFN-γ increased significantly only immediately after the intense exercise; IL-1β increased following both exercise intensities, although at 24 h it only remained elevated after the intense exercise; IL-12 only increased 24 h after the intense exercise, and IL-2 only showed a significant decrease following the moderate exercise. IL-6 increased immediately after both exercise intensities, but more so after moderate exercise. While IL-4 (an anti-inflammatory cytokine) increased following the moderate exercise, it decreased after the intense exercise. Both moderate and intense exercise increased norepinephrine and decreased cortisol, both of which returned to basal levels after 24 h. Only the intense exercise affected the epinephrine, oestradiol, and progesterone concentrations, with increases in epinephrine and oestradiol immediately after exercise, and a decrease in progesterone after 24 h. Conclusions: Both moderate and intense exercise stimulate the phagocytic process of neutrophils in sedentary women, but the profile of pro-/anti-inflammatory cytokine release seems to be better following the moderate exercise. The possible participation of stress (catecholamines and cortisol) and sex (oestradiol and progesterone) hormones in these intensity-dependent immune changes is discussed.

Exercise-induced neuroimmunomodulation is clearly accepted today. The present article reviews the main literature concerning the immunomodulatory capacity of catecholamines on the innate immune response during physical exercise, and presents our laboratory’s latest results on this topic. It is well known that the effects of exercise on the immune system are mediated by the ‘stress hormones and mediators’. Although catecholamines have usually been regarded as immunosuppressors, they may stimulate innate immune response mechanisms (such as phagocytic function) during exercise-induced stress, even without previous antigenic stimulation. The exercise-induced stimulation of the phagocytic response in particular and the innate responses in general have been considered as a prevention strategy of the athlete’s organism in order to prevent the entry and/or maintenance of antigens in a situation where the adaptive immune response seems to be depressed, and thus it has been suggested that catecholamines participate as a ‘stress mediator’ of these effects. Given this hypothesis, it is also suggested here that catecholamines may be the first ‘danger signal’ to the immune system during exercise-induced stress.

The influence of a single session of moderate exercise (45 min at 55% of VO(2 )max) performed by young sedentary men (23-25 years old) on the microbicidal capacity of neutrophils was compared by using both direct (killing of phagocytosed Candida albicans) and indirect (superoxide anion production measured by NBT reduction) techniques. In addition, the role of norepinephrine and heat shock protein (Hsp) 72 in the modulation of microbicide capacity of neutrophils was evaluated during the protocol of exercise and recovery period (24 h). No significant changes were found in the superoxide production after exercise. However, immediately after exercise there was an increase in the destruction of C. albicans, which remained higher than basal values 1 day later. This behaviour was similar to the changes found in the serum extracellular Hsp72 concentrations (an increase after exercise that remained higher than basal values 24 h later). In vitro, the raised physiological concentration of Hsp72 after exercise also increased the microbicide capacity of neutrophils with respect to controls and the values induced by the basal concentration of the protein. This indicates that Hsp72 is participating as a "stress mediator" of the stimulated microbicide activity during moderate exercise. However, norepinephrine is not mediating the increased killing of C. albicans during exercise.

Fibromyalgia (FM) is characterized in part by an elevated inflammatory status, and "modified exercise" is currently proposed as being a good therapeutic help for these patients. However, the mechanisms involved in the exercise-induced benefits are still poorly understood. The objective was to evaluate the effect of a single bout of moderate cycling (45 min at 55% VO2 max) on the inflammatory (serum IL-8; chemotaxis and O2 (-) production by neutrophils; and IL-1β, TNF-α, IL-6, IL-10, and IL-18 release by monocytes) and stress (cortisol; NA; and eHsp72) responses in women diagnosed with FM compared with an aged-matched control group of healthy women (HW). IL-8, NA, and eHsp72 were determined by ELISA. Cytokines released by monocytes were determined by Bio-Plex® system (LUMINEX). Cortisol was determined by electrochemoluminiscence, chemotaxis was evaluated in Boyden chambers and O2 (-) production by NBT reduction. In the FM patients, the exercise induced a decrease in the systemic concentration of IL-8, cortisol, NA, and eHsp72; as well as in the neutrophil's chemotaxis and O2 (-) production and in the inflammatory cytokine release by monocytes. This was contrary to the completely expected exercise-induced increase in all those biomarkers in HW. In conclusion, single sessions of moderate cycling can improve the inflammatory status in FM patients, reaching values close to the situation of aged-matched HW at their basal status. The neuroendocrine mechanism seems to be an exercise-induced decrease in the stress response of these patients.

Background Metabolic syndrome (MS) is a metabolic disorder associated with obesity, type-II diabetes, and "low grade inflammation", with the concomitant increased risk of cardiovascular events. Removal of the inflammatory mediator signals is a promising strategy to protect against insulin resistance, obesity, and other problems associated with MS such as cardiovascular disease. The aim of the present investigation was to determine the "inflammatory and stress status" in an experimental model of MS, and to evaluate the effect of a program of habitual exercise and the resulting training-induced adaptation to the effects of a single bout of acute exercise. Methods Obese Zucker rats (fa/fa) were used as the experimental model of MS, and lean Zucker rats (Fa/fa) were used for reference values. The habitual exercise (performed by the obese rats) consisted of treadmill running: 5 days/week for 14 weeks, at 35 cm/s for 35 min in the last month. The acute exercise consisted of a single session of 25-35 min at 35 cm/s. Circulating concentrations of IL-6 (a cytokine that regulates the inflammatory and metabolic responses), CRP (a systemic inflammatory marker), and corticosterone (CTC) (the main glucocorticoid in rats) were determined by ELISA, and that of noradrenaline (NA) was determined by HPLC. Glucose was determined by standard methods. Results The genetically obese animals showed higher circulating levels of glucose, IL-6, PCR, and NA compared with the control lean animals. The habitual exercise program increased the concentration of IL-6, PCR, NA, and glucose, but decreased that of CTC. Acute exercise increased IL-6, CRP, and NA in the sedentary obese animals, but not in the trained obese animals. CTC was increased after the acute exercise in the trained animals only. Conclusion Animals with MS present a dysregulation in the feedback mechanism between IL-6 and NA which can contribute to the systemic low-grade inflammation and/or hyperglycaemia of MS. An inappropriate exercise intensity can worsen this dysregulation, contributing to the metabolic, inflammatory, and stress disorders associated with MS. Habitual exercise (i.e., training) induces a positive adaptation in the response to acute exercise.