Abstract
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
Keywords
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- 1.
Data presented at the 2nd Iberoamerican Congreso of Neuroimmunomodulation (Madrid, Spain, 2007). Giraldo, E., Hinchado, M.D., García, J.J. and Ortega, E. (2006) Neuroimmunomodulation 13: 247–248 (Abstract); Giraldo, E., García, J.J., Hinchado, M.D., and Ortega, E. (2008) Exercise intensity-dependent changes in the inflammatory response in sedentary women: phagocytic process of neutrophils and pro-/anti-inflammatory cytokine balance. Role of neuroendocrine parameters. Neuroimmunomodulation (accepted for publication. DOI:10.1159/000212384).
- 2.
Data presented in the 2nd Iberoamerican Congress on Neuroinmunomodulation (Madrid, Spain, 2007; Giraldo et al., p. 98 of abstract book) and VI Iberoamerican Congress of Sports Medicine (Sevilla, Spain, 2007). Giraldo, E. and Ortega, E. (2007). Archivos de Medicina del Deporte 24, 353 (Abstract).
- 3.
Data presented in the VI Iberoamerican Congress of Sports Medicine (Sevilla, Spain, 2007). Hinchado, M.D. and Ortega, E (2007). Archivos de Medicina del Deporte 24, 352 (Abstract).
- 4.
Data presented in the VI Iberoamerican Congress of Sports Medicine (Sevilla, Spain, 2007). Giraldo, E. and Ortega, E (2007). Archivos de Medicina del Deporte 24, 352 (Abstract).
Abbreviations
- ACTH:
-
adrenocorticotropic hormone
- APC:
-
antigen presenting cells
- PBMC:
-
peripheral blood mononuclear cells
- eHsp72:
-
seventy two kilo Dalton extracellular heat shock protein
- ERK:
-
extracellular signal-regulated kinases
- fMLP:
-
formyl methionyl-leucyl-phenylalanine peptide
- IL-6:
-
interleukin-6
- LPS:
-
lipopolysaccharide
- NE:
-
norepinephrine
- NFkB:
-
nuclear factor kappa-light-chain-enhancer of activated B cells
- NK:
-
natural killer cells
- PI3K:
-
Phosphoinositide 3-kinases
- PRR’s:
-
pattern recognition receptors
- ROS:
-
reactive oxygen species
- SNS:
-
sympathetic nervous system
- SP:
-
stress proteins
- TLR 2:
-
toll like receptor 2
References
Asea, A. (2005) Stress proteins and initiation of immune response: chaperokine activity of hsp72. Exerc. Immunol. Rev. 11, 34–45.
Asea, A. (2006) Initiation of the immune response by extracellular Hsp72: chaperokine activity of Hsp72. Curr. Immunol. Rev. 2, 209–215.
Asea, A., Kraeft, S. K., Kurt-Jones, E. A. et al. (2000) HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine. Nat. Med. 6, 435–442.
Bausero, M. A., Gastpar, R., Multhoff, G. and Asea, A. (2005) Alternative mechanism by which IFN-γ enhances tumor recognition: active release of heat shock protein. J. Immunol. 175, 2900–2912.
Besedovsky, H. O. and Del Rey, A. (2007) Physiology of psychoneuroimmunology: a personal view. Brain Behav. Immun. 21, 34–44.
Blake, M. J., Udelsman, R., Feulner, G. J., Norton, D. D. and Holbrook, N. J. (1991) Stress-induced heat shock protein 70 expression in adrenal cortex: an adrenocorticotropic hormone-sensitive, age-dependent response. Proc. Natl. Acad. Sci. U. S. A. 88, 9873–9877.
Brenner, I., Shek, P. N., Zamecnik, J. and Shepard, R. J. (1998) Stress hormones and the immunological responses to heat and exercise. Int. J. Sports. Med. 19, 130–143.
Campisi, J. and Fleshner, M. (2003) Role of extracellular HSP72 in acute stress-induced potentiation of innate immunity in active rats. J. Appl. Physiol. 94, 43–52.
Campisi, J., Leem, T. H. and Fleshner, M. (2003) Stress-induced extracellular Hsp72 is a functionally significant danger signal to the immune system. Cell. Stress Chaperones 8, 272–286.
Caren, L. D. (1991) Effects of exercise on the human immune system. Does exercise influence susceptibility to infections? BioScience 41, 410–414.
Ceddia, M. A., Voss, E. W. and Woods, J. A. (2000) Intracellular mechanism responsible for exercise-induced suppression of macrophage antigen presentation. J. Appl. Physiol. 88, 804–810.
Chen, H. W., Yang, H. L., Jing, H. H. et al. (1995) Synthesis of Hsp72 induced by exercise in high temperature. Chin. J. Physiol. 38, 241–246.
Clayton, A., Turkes, A., Navabi, H., Mason, M. D. and Tabi, Z. (2005) Induction of heat shock proteins in B-cell exosomes. J. Cell Sci. 118, 3631–3638.
Cohen, L. A., Kendall, M. E., Meschter, C., Epstein, M. A., Reinhandt, J. and Zang, E. (1993) Inhibition of rat mammary tumorigenesis by voluntary exercise. In Vivo 7, 151–158.
Elenkov, I. J. and Chrousos, G. P. (2002) Stress hormones, proinflammatory and antiinflammatory cytokines, and autoimmunity. Ann. N. Y. Acad. Sci. 966, 290–303.
Elenkov, I. J., Wilder, R. L., Chrousos, G. P. and Vizi, E. S. (2000) The sympathetic nerve – an integrative interface between two supersystems: the brain and the immune system. Pharmacol. Rev. 52, 595–638.
Febbraio, M. A., Steensberg, A., Walsh, R. et al. (2002) Reduced glycogen availability is associated with an elevation in HSP72 in contracting human skeletal muscle. J. Physiol. 538, 911–917.
Fehrenbach, E., Niess, A. M., Voelker, K., Northoff, H. and Mooren, F. C. (2005) Exercise intensity and duration affect blood soluble HSP72. Int. J. Sports Med. 26, 552–557.
Fitzgerald, L. (1988) Exercise and the immune system. Immunol. Today 9, 337–339.
Fleshner, M., Campisi, J., Amiri, L. and Diamond, D. M. (2004) Cat exposure induces both intra- and extracellular Hsp72: the role of adrenal hormones. Psychoneuroendocrinology 29, 1142–1152.
Fleshner, M., Campisi, J. and Johnson, J. D. (2003) Can exercise stress facilitate innate immunity? A functional role for stress-induced extracellular Hsp72. Exerc. Immunol. Rev. 9, 6–24.
Fleshner, M. and Johnson, J. D. (2005) Endogenous extra-cellular heat shock protein 72: releasing signal(s) and function. Int. J. Hyperthermia. 21, 457–471.
Forner, M. A., Barriga, C., Rodríguez, A. B. and Ortega, E. (1995) A study of the role of corticosterone as a mediator in exercise-induced stimulation of murine macrophage phagocytosis. J. Physiol. 488, 789–794.
Gallucci, S., Lolkema, M. and Matzinger, P. (1999) Natural adjuvants: endogenous activators of dendritic cells. Nat. Med. 5, 1249–1255.
García, J. J., del Carmen Sáez, M., De la Fuente, M. and Ortega, E. (2003a) Noradrenaline and its end metabolite 3-methoxy-4-hydroxyphenylglycol inhibit lymphocyte chemotaxis: role of alpha- and beta-adrenoreceptors. Mol. Cell. Biochem. 254, 305–309.
García, J. J., del Carmen Sáez, M., De la Fuente, M. and Ortega, E. (2003b) Regulation of phagocytic process of macrophages by noradrenaline and its end metabolite 4-hydroxy-3 metoxyphenyl-glycol. Role of alpha- and beta-adrenoreceptors. Mol. Cell. Biochem. 254, 299–304.
Gastpar, R., Gehrmann, M., Bausero, M. A. et al. (2005) Heat shock protein 70 surfacepositive tumor exosomes stimulate migratory and cytolytic activity of natural killer cells. Cancer Res. 65, 5238–5247.
Giraldo, E., Hinchado, M. D., Garcia, J. J. and Ortega, E. (2008) Influence of gender and oral contraceptives intake on innate and inflammatory response. Role of neuroendocrine factors. Mol. Cell. Biochem. 313, 147–153.
Heneka, M. T., Gavrilyuk, V., Landreth, G. E., O’Banion, M. K., Weinberg, G. and Feinstein, D. L. (2003) Noradrenergic depletion increases inflammatory responses in brain: effects on IkappaB and HSP70 expression. J. Neurochem. 85, 387–398.
Hennigan, S. M., Wang, J. H., Redmond, H. P. and Bouchier-Hayes, D. (1999) Neutrophils heat shock proteins expression and activation correlated with increased apoptosis following transmigration through the endothelial barrier. Shock 12, 32–38.
Hightower, L. E. and Guidon, P. T., Jr. (1989) Selective release from cultured mammalian cells of heat-shock (stress) proteins that resemble glia-axon transfer proteins. J. Cell. Physiol. 138, 257–266.
Hoffman-Goetz, L. and Husted, J. (1994) Exercise and breast cancer: review and critical analysis of the literature. Can. J. Appl. Physiol. 19, 237–252.
Hoffman-Goetz, L. and Pedersen, B. K. (1994) Exercise and the immune system: a model of stress response? Immunol. Today 15, 382–387.
Horowitz, M. and Robinson, S. D. (2007) Heat shock proteins and the heat shock response during hyperthermia and its modulation by altered physiological conditions. Prog. Brain. Res. 162, 433–446.
Hunter-Lavin, C., Davies, E. L., Bacelar, M. M., Marshall, M. J., Andrew, S. M. and Williams, J. H. (2004) Hsp70 release from peripheral blood mononuclear cells. Biochem. Biophys. Res. Commun. 324, 511–517.
Ignatowski, T. A., Gallant, S. and Spengler, R. N. (1996) Temporal regulation by adrenergic receptor stimulation of macrophage (M phi)-derived tumor necrosis factor (TNF) production post-LPS challenge. J. Neuroimmunol. 65, 107–117.
Ilback, N. G., Friman, G., Beisel, W. R., Johnson, A. J. and Berendt, R. F. (1984) Modifying effects of exercise on clinical course and biochemical response of the myocardium in influenza and tularaemia in mice. Infect. Immunol. 45, 498–504.
Johnson, J. D., Campisi, J., Sharkey, C. M., Kennedy, S. L., Nickerson, M. and Fleshner, M. (2005) Adrenergic receptors mediate stress-induced elevations in extracellular Hsp72. J. Appl. Physiol. 99, 1789–1795.
Johnson, J. D. and Fleshner, M. (2006) Releasing signals, secretory pathways, and immune function of endogenous extracellular heat shock protein 72. J. Leukoc. Biol. 79, 425–434.
Khansari, D. N., Murgo, A. J. and Faith, R. E. (1990) Effect of stress on the immune system. Immunol. Today 11, 170–175.
Kovalchin, J. T., Wang, R., Wagh, M. S., Azoulay, J., Sanders, M. and Chandawarkar, R. Y. (2006) In vivo delivery of heat shock protein 70 accelerates wound healing by up-regulating macrophage-mediated phagocytosis. Wound Repair Regen. 14, 129–137.
Kregel, K. C. (2002) Heat shock proteins: modifying factors in physiological stress responses and acquired thermotolerance. J. Appl. Physiol. 92, 2177–2186.
Lancaster, G. I. and Febbraio, M. A. (2005) Exosome-dependent trafficking of HSP70: a novel secretory pathway for cellular stress proteins. J. Biol. Chem. 280, 23349–23355.
Lancaster, G. I., Møller, K., Nielsen, B., Secher, N. H., Febbraio, M. A. and Nybo, L. (2004) Exercise induces the release of heat shock protein 72 from the human brain in vivo. Cell. Stress Chaperones 9, 276–280.
Locke, M. and Noble, E. G. (1995) Stress proteins: the exercise response. Can. J. Appl. Physiol. 20, 155–167.
Mackinnon, L. T. Exercise and immunology: present and future directions. In: Exercise and Immunology, L. T. Mackinon, ed., Human Kinetics Books, Champaign, IL, 1992, pp. 85–90.
Macneil, B. and Hoffman-Goetz, L. (1993) Exercise training and tumor metastasis in mice: influence of time of exercise onset. Anticancer Res. 13, 2085–2088.
Madden, K. S. and Livnat, S. Catecholamines action and immunologic reactivity. In: Psychoneuroimmunology., R. Ader, D. L. Felten, and N. Cohen, eds., Academic Press, New York, 1991, pp. 283–305.
Maloyan, A. and Horowitz, M. (2002) β-Adrenergic signaling and thyroid hormones affect HSP72 expression during heat acclimation. J. Appl. Physiol. 93, 107–115.
Marini, M., Frabetti, F., Musiani, D. and Franceschi, C. (1996) Oxygen radicals induce stress proteins and tolerance to oxidative stress in human lymphocytes. Int. J. Radiat. Biol. 70, 337–350.
Matz, J. M., LaVoi, K. P. and Blake, M. J. (1996) Adrenergic regulation of the heat shock response in brown adipose tissue. J. Pharmacol. Exp. Ther. 277, 1751–1758.
Matzinger, P. (1994) Tolerance, danger and the extended family. Ann. Rev. Immunol. 12, 991–1045.
Matzinger, P. (1998) An innate sense of danger. Semin. Immunol. 10, 399–415.
Meltzer, J. C., MacNeil, B. J., Sanders, V. et al. (2004) Stress-induced suppression of in vivo splenic cytokine production in the rat by neural and hormonal mechanisms. Brain Behav. Immun. 18, 262–273.
Nagatomi, R., Kaifu, T., Okutsu, M., Zhang, X., Kanemi, O. and Ohmori, H. (2000) Modulation of the immune system by the autonomic nervous system and its implication in immunological changes after training. Exerc. Immunol. Rev. 6, 54–74.
Nance, D. M. and Sanders, V. M. (2007) Autonomic innervation and regulation of the immune system 1987–2007. Brain Behav. Immun. 21, 736–745.
Ogura, Y., Naito, H., Akin, S. et al. (2008) Elevation of body temperature is an essential factor for exercise-increased extracellular heat shock protein 72 level in rat plasma. Am. J. Physiol. Regul. Integr. Comp. Physiol. 294, R1600–R1607.
Ortega, E. (1994) Physiological and biochemistry: influence of exercise on phagocytosis. Int. J. Sports Med. 15, 5172–5178.
Ortega, E. (2003) Neuroendocrine mediators in the modulation of phagocytosis by exercise: physiological implications. Exerc. Immunol. Rev. 9, 70–94.
Ortega, E., Collazos, M. E., Barriga, C. and De la Fuente, M. (1992) Stimulation of the phagocytic function in guinea pig peritoneal macrophages by physical activity stress. Eur. J. Appl. Physiol. Occup. Physiol. 64, 323–327.
Ortega, E., Forner, M. A. and Barriga, C. (1997) Exercise-induced stimulation of murine macrophage chemotaxis: role of corticosterone and prolactin as mediators. J. Physiol. 498, 729–734.
Ortega, E., García, J. J. and De la Fuente, M. (2000a) Modulation of adherence and chemotaxis of macrophages by norepinephrine. Influence of ageing. Mol. Cell. Biochem. 203, 113–117.
Ortega, E., García, J. J., Marchena, J. M., Barriga, C. and Rodriguez, A. B. (2005a) Phagocytes may counteract the “open window” situation during a bout of moderate exercise performed by sedentary individuals: role of noradrenaline. J. Appl. Biomed. 3, 75–82.
Ortega, E., García, J. J., Sáez, M. C. and De la Fuente, M. (2000b) Changes with aging in the modulation of macrophages by norepinephrine. Mech. Ageing Dev. 118, 103–114.
Ortega, E., Giraldo, E., Hinchado, M. D. et al. (2006) Role of Hsp72 and norepinephrine in the moderate exercise-induced stimulation of neutrophils’ microbicide capacity. Eur. J. Appl. Physiol. 98, 250–255.
Ortega, E., Giraldo, E., Hinchado, M. D., Martín, L., García, J. J. and De la Fuente, M. (2007) Neuroimmunomodulation during exercise: role of catecholamines as “stress mediator” and/or “danger signal” for the innate immune response. Neuroimmunomodulation 14, 206–212.
Ortega, E., Hinchado, M. D., Martín-Cordero, L. and Asea, A. (2009) The effect of stress-inducible extracelular Hsp72 on human neutrophils chemotaxis: the role during acute intense exercise. Stress 12, 240–249.
Ortega, E., Marchena, J. M., García, J. J. et al. (2001) Phagocytic function in cyclists: correlation with catecholamines and cortisol. J. Appl. Physiol. 91, 1067–1072.
Ortega, E., Marchena, J. M., García, J. J., Barriga, C. and Rodríguez, A. B. (2005b) Norepinephrine as mediator in the stimulation of phagocytosis induced by moderate exercise. Eur. J. Appl. Physiol. 93, 714–718.
Peake, J., Peiffer, J. J., Abbiss, C. R. et al. (2008) Body temperature and its effect on leukocyte mobilization, cytokines and markers of neutrophil activation during and after exercise. Eur. J. Appl. Physiol. 102, 391–401.
Pedersen, B. K. and Hoffman-Goetz, L. (2000) Exercise and the immune system: regulation, inegration and adaptation. Physiol. Rev. 80, 1055–1081.
Pedersen, B. K., Rhode, T. and Ostrowski, K. (1998) Recovery of the immune system after exercise. Acta. Physiol. Scand. 162, 325–332.
Pittet, J. F., Lee, H., Morabito, D., Howard, M. B., Welch, W. J. and Mackersie, R. C. (2002) Serum levels of Hsp 72 measured early after trauma correlate with survival. J. Trauma. 52, 611–617.
Pockley, A. G. (2002) Heat shock proteins, inflammation, and cardiovascular disease. Circulation 105, 1012–1017.
Pockley, A. G. (2003) Heat shock proteins as regulators of the immune response. Lancet 362, 469–476.
Pockley, A. G., Georgiades, A., Thulin, T., de Faire, U. and Frostegard, J. (2003) Serum heat shock protein 70 levels predict the development of atherosclerosis in subjects with established hypertension. Hypertension 42, 235–238.
Prohászka, Z. and Füst, G. (2004) Immunological aspects of heat-shock proteins-the optimum stress of life. Mol. Immunol. 41, 29–44.
Sáez, M. C., Barriga, C., García, J. J., Rodríguez, A. B. and Ortega, E. (2007) Exercise-induced stress enhances mammary tumor growth in rats: beneficial effect of the hormone melatonin. Mol. Cell. Biochem. 294, 19–24.
Saez, M. C., Garcia, J. J., De la Fuente, M. and Ortega, E. (2002) Modulation of superoxide anion levels of macrophages from young-adult and old mice by the norepinephrine metabolite, 4-hydroxy-3-methoxyphenyl-glycol. Exp. Gerontol. 37, 395–400.
Sanders, V. M. (2006) Interdisciplinary research: noradrenergic regulation of adaptive immunity. Brain Behav. Immun. 20, 1–8.
Sun, L., Chang, J., Kirchhoff, S. R. and Knowlton, A. A. (2000) Activation of HSF and selective increase in heat-shock proteins by acute dexamethasone treatment. Am. J. Physiol. Heart. Circ. Physiol. 278, H1091–H1097.
Thompson, H. J. (1994) Effect of exercise intensity and duration on the induction of mammary carcinogenesis. Cancer Res. 54, 1960s–1963s.
Udelsman, R., Li, D. G., Stagg, C. A., Gordon, C. B. and Kvetnansky, R. (1994) Adrenergic regulation of adrenal and aortic heat shock protein. Surgery 116, 177–182.
Van Eden, W., van der Zee, R., Paul, A. et al. (1998) Do heat shock proteins control the balance of T-cell regulation in inflammatory diseases? Immunol. Today 19, 303–307.
Walsh, R. C., Koukolas, I., Garnham, A., Moseley, P. L., Hargreaves, M. and Febbraio, M. A. (2001) Exercise increases serum Hsp72 in humans. Cell. Stress Chaperones 6, 386–393.
Wang, R., Town, T., Gokarn, V., Flavell, R. A. and Chandawarkar, R. Y. (2006) Hsp70 enhances macrophage phagocytosis by interaction with lipid Raft-associated TLR7 and upregulating p38 MAPK and PI3K pathways. J. Burg. Res. 136, 58–69.
Whitham, M. and Fortes, M. B. (2008) Heat shock protein 72: release and biological significance during exercise. Front. Biosci. 13, 1328–1339.
Whitham, M., Walker, G. J. and Bishop, N. C. (2006) Effect of caffeine supplementation on the extracellular heat shock protein 72 response to exercise. J. Appl. Physiol. 101, 1222–1227.
Wilder, R. and Elenkov., I. (2001) Ovarian and sympathoadrenal hormones, pregnancy and autoimmunity diseases. In: Psyconeuroimmunology, Vol. 2, R. Ader, D. L. Felten, and N. Cohen, eds., Academic Press, New York, pp. 421–431.
Woods, J. A. (2000) Exercise and neuroendocrine modulation of macrophage function. Int. J. Sports Med. 21, 24–30.
Acknowledgments
This work has been partially supported by Junta de Extremadura III PRI06A172 and MICINN-FEDER DEP2006-56187-C04-03, DEP 2009–10041 as well as by fellows from Consejería de Infraestructura y Desarrollo Tecnológico y Fundación Valhondo de Extremadura (Spain).
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Ortega, E., Giraldo, E., Hinchado, M.D., Martín-Cordero, L., García, J.J. (2010). 72 kDa Extracellular Heat Shock Protein (eHsp72), Norepinephrine (NE), and the Innate Immune Response Following Moderate Exercise. In: Asea, A., Pedersen, B. (eds) Heat Shock Proteins and Whole Body Physiology. Heat Shock Proteins, vol 5. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-3381-9_19
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