E. Giraldo

Exercise intensity-dependent changes in the inflammatory response in sedentary women: role of neuroendocrine parameters in the neutrophil phagocytic process and the pro-/anti-inflammatory cytokine balance.

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.

Aquatic exercise improves the monocyte pro‐ and anti‐inflammatory cytokine production balance in fibromyalgia patients

Current hypotheses of the etiology of fibromyalgia (FM) include inflammatory disorders. We evaluated the effect of a pool‐aquatic exercise program (8 months, two weekly 60‐min sessions) on the inflammatory cytokine production by isolated monocytes, and on the serum concentration of C‐reactive protein (CRP), in a group of female FM patients. Monocytes from FM patients released more IL‐1β, TNFα, IL‐6, and IL‐10 than those from an age‐matched control group of healthy women (HW). This inflammatory disorder in FM women was also manifested by high circulating concentrations of CRP. Increased IL‐6 with a concomitant decreased TNFα spontaneous release was found after 4 months (midway through) of the exercise program. At the end of the program (8 months), monocytes from FM patients showed diminished spontaneous production of pro‐/anti‐inflammatory cytokines, with a similar spontaneous release of IL‐1β and IL‐6 to that of HW, but a lower production of TNFα and higher of IL‐10. Lipopolysaccharide‐induced production of IL‐1β, TNFα, IL‐6, and IL‐10 also decreased at the end of the exercise program, although IL‐10 remained higher than HW. The anti‐inflammatory effect of the exercise program was also corroborated by a decrease in the circulating CRP concentration. Exercise also improved the health‐related quality of life of FM patients.

Neuroimmunomodulation during Exercise: Role of Catecholamines as ‘Stress Mediator’ and/or ‘Danger Signal’ for the Innate Immune Response

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.

72 kDa Extracellular Heat Shock Protein (eHsp72), Norepinephrine (NE), and the Innate Immune Response Following Moderate Exercise

It is now well known that both norepinephrine (NE) and 72 kDa extracellular heat shock protein (eHsp72) are released during stress, and that they can activate the immune system, mainly the innate immune response, even before a pathogen challenge. This is one reason why they have been postulated as “stress messengers or mediators” or “danger signals” for the immune system during stress. Exercise constitutes a stress because it alters the organism’s homeostasis. Indeed, most of the exercise-induced changes in the immune system (including moderate exercise) are mediated by stress hormones and proteins, including NE and eHsp72. In this chapter, we present the latest studies performed in our laboratory about the role of NE and eHsp72 in the moderate-exercise-induced stimulation of neutrophil function, reviewing the main literature on the interaction between NE and Hsp72 not only in stimulating the innate immune response but also in the role of NE as a triggering signal in the stress-induced systemic release of eHsp72, particularly following moderate exercise. We also discuss the immunophysiological relevance of these interactions, as well as the optimal level of exercise that improves, but not impairs, the immune function by stimulating innate and/or inflammatory response mechanisms

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 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. J. Cell. Physiol. 227: 604–608, 2012.

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. J. Cell. Physiol. 228: 1902–1906, 2013.