Showing papers in "Exercise Immunology Review in 2005"

Characterization of inflammatory responses to eccentric exercise in humans.

Abstract: Eccentric exercise commonly results in muscle damage. The primary sequence of events leading to exercise-induced muscle damage is believed to involve initial mechanical disruption of sarcomeres, followed by impaired excitation-contraction coupling and calcium signaling, and finally, activation of calcium-sensitive degradation pathways. Muscle damage is characterized by ultrastructural changes to muscle architecture, increased muscle proteins and enzymes in the bloodstream, loss of muscular strength and range of motion and muscle soreness. The inflammatory response to exercise-induced muscle damage is characterized by leukocyte infiltration and production of pro-inflammatory cytokines within damaged muscle tissue, systemic release of leukocytes and cytokines, in addition to alterations in leukocyte receptor expression and functional activity. Current evidence suggests that inflammatory responses to muscle damage are dependent on the type of eccentric exercise, previous eccentric loading (repeated bouts), age and gender. Circulating neutrophil counts and systemic cytokine responses are greater after eccentric exercise using a large muscle mass (e.g. downhill running, eccentric cycling) than after other types of eccentric exercise involving a smaller muscle mass. After an initial bout of eccentric exercise, circulating leukocyte counts and cell surface receptor expression are attenuated. Leukocyte and cytokine responses to eccentric exercise are impaired in elderly individuals, while cellular infiltration into skeletal muscle is greater in human females than males after eccentric exercise. Whether alterations in intracellular calcium homeostasis influence inflammatory responses to muscle damage is uncertain. Furthermore, the effects of antioxidant supplements are variable, and the limited data available indicates that anti-inflammatory drugs largely have no influence on inflammatory responses to eccentric exercise. In this review, we compare local versus systemic inflammatory responses, and discuss some of the possible mechanisms regulating the inflammatory responses to exercise-induced muscle damage in humans.

Stress Proteins and Initiation of Immune Response: Chaperokine activity of Hsp72

Abstract: From its original description as solely an intracellular molecular chaperone, heat shock proteins have now been shown to function as initiators of the host's immune response. Although the exact mechanism by which intracellular heat shock proteins leave cells is still incompletely understood, recent work from several labs suggest that heat shock proteins are released by both passive (necrotic) and active (physiological) mechanisms. Binding to specific surface receptors is a prerequisite for the initiation of an immune response. To date, several cell surface proteins have been described as the receptor for seventy kilo-Dalton heat shock protein (Hsp70) including Toll-like receptors 2 and 4 with their cofactor CD14, the scavenger receptor CD36, the low-density lipoprotein receptor-related protein CD91, the C-type lectin receptor LOX-1, and another member of the scavenger super-family SR-A plus the co-stimulatory molecule, CD40. Binding of Hsp70 to these surface receptors specifically activates intracellular signaling cascades, which in turn exert immunoregulatory effector functions; a process known as the chaperokine activity of Hsp70. This review will highlight recent advances in understanding the mechanism by which Hsp70 initiates the host's immune response.

Immunostimulatory functions of membrane-bound and exported heat shock protein 70.

Abstract: In the search for tumor-specific antigens, microbial and eukaryotic heat shock proteins (HSP) have been identified. Intracellularly, HSPs function as molecular chaperones supporting folding and transport of a great variety of polypeptides and proteins under normal physiological conditions and following stress stimuli. Furthermore, interferon-gamma and elevated body temperature induced by exercise have been found to increase serum levels of HSPs in humans. Extracellularly localized or plasma membrane-bound HSPs elicit a potent anti-cancer immune response mediated either by the adaptive or innate immune system. Following uptake of HSP (HSP70 and gp96)-peptide complexes by antigen presenting cells (APCs) and "cross-presentation" of HSP-chaperoned peptides on MHC class I molecules, a CD8-specific T cell response is induced. Apart from chaperoning tumor-specific peptides, HSPs per se provide activatory signals for the innate immune system. Binding of peptide-free HSP70 to APCs via Toll-like receptors (TLRs) initiates the secretion of pro-inflammatory cytokines and thus results in a broad non-specific immunostimulation. An unusual membrane localization of Hsp70, the major heat-inducible member of the HSP70 family, on tumor cells but not on corresponding normal tissues was found to act as a tumor-specific recognition structure for natural killer (NK) cells. Soluble as well as cell membrane-bound HSP70 can directly activate the cytolytic and migratory capacity of NK cells. APCs and tumor cells actively release HSP70s in lipid vesicles with biophysical properties of exosomes. These HSP70-presenting exosomes are thought to stimulate the adaptive and innate immune system in vivo. Taken together, depending on their intra/extracellular localization, peptide loading status, origin and route of application, HSPs either exert immune activation as danger signals in cancer immunity or protect cells from lethal damage induced by exogenous stress stimuli.

Fiber type specific expression of TNF-alpha, IL-6 and IL-18 in human skeletal muscles.

Abstract: Skeletal muscle is now recognized as an endocrine organ with the capacity to produce signal peptides in response to muscle contractions. Here we demonstrate that resting healthy human muscles express cytokines in a fiber type specific manner. Human muscle biopsies from seven healthy young males were obtained from m. triceps, m. quadriceps vastus lateralis and m. soleus. Type I fibers contributed (mean +/- SE) 24.0 +/- 2.5% in triceps of total fibers, 51.3 +/- 2.4% in vastus and 84.9 +/- 22% in soleus. As expected, differences in the fiber type composition were accompanied by marked differences between the three muscles with regard to MHC I and MHC IIa mRNA expression. Immunohistochemistry demonstrated that tumor necrosis factor (TNF)-alpha and interleukin (IL)-18 were solely expressed by type II fibers, whereas the expression of IL-6 was more prominent in type I compared to type II fibers. The fiber type specificity was found in triceps, vastus and soleus indicating that the level of daily muscle activity did not influence basal cytokine expression. The specificity of cytokine expression in different muscle fiber types in healthy young males suggests that cytokines may play specific regulatory roles in normal physiology.

Altitude, exercise and immune function.

Abstract: Little is known with regard to how acute and chronic high altitude exposure effects immune function. Hypoxia is an environmental stressor that is known to elicit alterations in both the autonomic nervous system and endocrine function. Alterations in these systems can have an immediate as well as a longer lasting impact on immune function. Studies from the summit of Pikes Peak (4300 m) have indicated a strong alpha- & beta-adrenergic component in the regulation of immune function at altitude that can persist weeks after initial exposure. Specifically, interleukin (IL)-6 is elevated with acute altitude exposure primarily mediated via beta-adrenergic stimulation and remains elevated for several weeks as a result of alpha-adrenergic activation. When the added stress of physical exercise is combined with that of hypoxia, a more pronounced impact on immune function is observed compared to that of either exercise or hypoxia alone. A popular training paradigm currently employed by endurance athletes to enhance performance involves living at high altitude while training at low altitude. The concept entails incorporating the physiologic and metabolic adaptations associated with chronic high altitude exposure (increase in RBC, mitochondrial oxidative capacity, capillary density, etc) while training at a lower altitude allowing for the maintenance of a high absolute training intensity. Others have demonstrated that a short-term application (18 days) of the live high-train low paradigm results in suppression of the mucosal immune system as indicated by a cumulative decline in salivary IgA levels. Taken together, the majority of evidence suggests a potential additive effect of combined hypoxia and exercise in transiently suppressing immune function, at least in the short-term. Implications for the athletes and training are addressed.

Mechanisms of stress-induced cellular HSP72 release: implications for exercise-induced increases in extracellular HSP72.

Abstract: The heat shock proteins are a family of highly conserved proteins with critical roles in maintaining cellular homeostasis and in protecting the cell from stressful conditions. While the critical intracellular roles of heat shock proteins are undisputed, evidence suggests that the cell possess the necessary machinery to actively secrete specific heat shock proteins in response to cellular stress. In this review, we firstly discuss the evidence that physical exercise induces the release of heat shock protein 72 from specific tissues in humans. Importantly, it appears as though this release is the result of an active secretory process, as opposed to non-specific processes such as cell lysis. Next we discuss recent in vitro evidence that has identified a mechanistic basis for the observation that cellular stress induces the release of a specific subset of heat shock proteins. Importantly, while the classical protein secretory pathway does not seem to be involved in the stress-induced release of HSP72, we discuss the evidence that lipid-rafts and exosomes are important mediators of the stress-induced release of HSP72.

Paediatric exercise immunology: health and clinical applications.

Abstract: Considerable advances have been made in exercise immunology over the last two decades, and it is becoming evident that many of the health benefits of regular physical activity may be directly related to activation of the immune system. The number of investigations devoted to the paediatric population, however, remains low, and our understanding of the interaction between acute and chronic exercise and the immune system in youth is, therefore, relatively deficient. The purpose of this review is to disseminate the existing knowledge in the area of paediatric exercise immunology and to discuss growth-related issues with respect to exercise and the immune system in health and disease. In general, healthy children experience smaller overall perturbations to the immune system in response to an acute bout of exercise, and demonstrate a faster recovery of the immune system following exercise. The immune effects of chronic exercise and/or exercise training in healthy children and adolescents have not been well-documented, and there is only limited evidence to suggest that moderate to high levels of habitual physical activity are associated with a reduction in the incidence of infection and illness in youth. A number of paediatric clinical conditions expressing a strong immune component are also discussed in the context of acute exercise effects and the potential benefits of enhanced physical activity. Given the linkage between childhood health and adult disease, paediatric exercise immunology represents a fruitful area for future study.

CDNA-microarray analysis as a research tool for expression profiling in human peripheral blood following exercise.

Abstract: Exhausting endurance exercise has strong effects on the immune system. Changes have been shown in the cellular composition of peripheral blood and in gene expression within those cells. In this study, custom-made cDNA microarrays focused on inflammation were used to analyze gene expression blood cells obtained from eight half-marathon runners before (t0), immediately after (t1) and 24 hours after exercise (t2). The microarrays that were used contained 384 different cDNAs spotted in triplicate. Differentially-regulated gene expression was analyzed using a simple rule-based clustering. Comparing t1 vs. t0, and t2 vs. t0, 36 and 21 sequences respectively, showed a consistent pattern of changes in all eight athletes. Taken together, the pattern of these modified genes can be viewed as a "gene expression fingerprint" for each time point in response to a half marathon. The known and novel genes identified here represent targets for further molecular characterization of the complex reaction of the body to an exhaustive challenge. These data suggest that gene expression fingerprints can serve as a powerful research tool to design novel strategies for diagnosis and treatment of exercise related injury and stress.

Association between LDL-cholesterol, statin therapy, physical activity and inflammatory markers in patients with stable coronary heart disease.

Abstract: Evidence suggests that inflammatory parameters such as high sensitive C-reactive protein (hs-CRP), interleukin-6 (IL-6), serum amyloid-A (SAA) and fibrinogen (Fib) are associated with cardiovascular morbidity and mortality. In this study we investigated the association between LDL-cholesterol (LDL-C), lipid lowering drug therapy (LLD) and inflammatory markers in 436 subjects (age 64,2 +/- 4.1 yr, BMI 27,6 +/- 3,9 kg/m2) with coronary heart disease, participating in outpatient exercise groups for cardiac rehabilitation. In a subgroup analysis (n=229), we looked at the respective effects of physical activity (PA) alone and in combination with LLD. For the whole group the levels of inflammatory markers were: hs-CRP 0,31 +/- 0,4 mg/dl; IL-6 2,04 +/- 1,6 pg/ml; SAA 6,26 +/- 14 mg/l; Fib 381 +/- 97 mg/dl. Compared to patients without LLD, those with LLD showed modestly lower concentrations for CRP (-7%) and IL-6 (-12%), (p 100 mg/dl. Patients with a high level of PA (PA > or = 3 times/week) exhibited significantly lower values for CRP (-18%), Fib (-11%) and SAA (-37%) (p<0.01, respectively) than patients with a low level of PA (< or = 1 time/week). The combination of a high level of PA, and intake of LLD further reduced CRP (-37%) and SAA (-45%), with no additional decrease in Fib (-10%) (p<0.01, respectively) compared to patients with a low level of PA and taking LLD. The data from this cross-sectional study suggest that factors such as LLD, LDL-C (< 100 mg/dl), and a high level of physical activity are associated with lower levels of inflammatory markers in patients with coronary heart disease. Particularly with respect to CRP and SAA values, a high level of PA in combination with LLD, showed the most pronounced effects. The proof of causality of these findings should further be investigated in randomized controlled trials.