Altered profile of chemokines in fibromyalgia patients.

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 < 0.001), MIG (P < 0.001), MDC (P < 0.01), I-TAC (P < 0.01) and eotaxin (P < 0.05). No differences were found in the circulating concentrations of PARC and HCC-4 (homoeostatic chemokines). 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.

Combined activity of post-exercise concentrations of NA and eHsp72 on human neutrophil function: role of cAMP.

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.

Inflammatory/stress feedback dysregulation in women with fibromyalgia.

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-1ß, 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-1ß, 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.

Adrenoreceptors are involved in the stimulation of neutrophils by exercise-induced circulating concentrations of Hsp72: cAMP as a potential "intracellular danger signal".

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 ß-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.

The interleukin-6 and noradrenaline mediated inflammation-stress feedback mechanism is dysregulated in metabolic syndrome: effect of exercise.

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, CRP, 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.