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The Role of Exercise Stress and Catecholamines in Immunity

The Role of Exercise Stress and Catecholamines in Immunity. Erika Vielmas February 23, 2009 Biol 520. Background Information. Catecholamines (CAs). Catecholamines Known as epinephrine and norepinephrine (adrenaline/noradrenaline). Water soluble hormones that circulate in the blood.

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The Role of Exercise Stress and Catecholamines in Immunity

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  1. The Role of Exercise Stress and Catecholamines in Immunity Erika Vielmas February 23, 2009 Biol 520

  2. Background Information

  3. Catecholamines (CAs) Catecholamines Known as epinephrine and norepinephrine (adrenaline/noradrenaline). Water soluble hormones that circulate in the blood. Produced from chromaffin cells; neuroendocrine cells found in the adrenal medulla. β-adrenergic receptors: G-coupled protein receptors that are targets for CAs. Benschop et al 1994 http://en.wikipedia.org/wiki/Adrenergic_receptor

  4. Catecholamine Synthesis +NH3 +NH3 +NH3 CH2-CH-COO- OH CH-CH2 CH2-CH2 Tyrosine hydroxylase Aromatic amino acid decarboxylase OH Dopamine Tyrosine OH Dopamine β-Hydroxylase Norepinephrine OH Epinephrine OH H2N+-CH3 OH CH-CH2 OH OH OH Phenylethanolamine N-methyltransferase Nelson & Cox 2005

  5. The Hypothalamic–Pituitary–Adrenal (HPA) Axis PVN of the hypothalamus releases Cortico releasing hormone (CRH). CRH stimulates the anterior pituitary gland to release adrenocorticotropin (ACTH) hormone into circulation. The ACTH induces the adrenal glands to synthesize and secrete glucocorticoids and catecholamines. PVN A.P www.ott.zynet.co.uk/.../images/encephf1.gif Webster-Marketon et al 2008

  6. Sympathetic Nervous System The SNS is activated by the secretion of acetylcholine from the pre ganglionic sympathetic fibers in the adrenal medulla. SNS activation induces secretion of epinephrine into blood circulation. Norepinephrine is released from the nerve terminals in the vicinity of immune cells. Webster-Marketon et al 2008 users.rcn.com/.../BiologyPages/P/PNS.html

  7. CAs can be Synthesized by Immune Cells For many years, CAs were believed to be synthesized only by neurons and endocrine cells. Recent studies suggest that lymphocytes and mature CD3 T- cells can synthesize and secrete CAs. Cells need high levels of norepinephrine to stimulate the production of more CAs. Leposavic et al 2008

  8. Lymphocyte Differentiation Mammalian stem cells differentiate into several kinds of blood cells within the bone marrow by a process called haematopoiesis. All lymphocytes originate from a common lymphoid progenitor before differentiating into their distinct lymphocyte types. The formation of lymphocytes is known as lymphopoiesis. http://en.wikipedia.org/wiki/Lymphocyte

  9. www.textbookofbacteriology.net

  10. Natural Killer Cells (NK) Natural Killer Cellsare large granular lymphoid-like cells important in innate immunity. NK cells are produced in the bone marrow. These cells can detect virus-infected cells without having any antigen specificity . (“natural killer”). To control their cytotoxic activity, NK cells possess two types of surface receptors: activating receptors and inhibitory receptors. Inhibitory receptors recognize MHC I molecules and activating receptors recognize interferons and cytokines(which may be caused by stress); interferon γ (INF-γ) and interleukin-2 (IL-2) . 80% of NK cells express CD8. Calcagni et al 2006 Webster-Marketon et al 2008 http://jem.rupress.org/cgi/content/abstract/190/7/1005

  11. Two Functionally Distinct Cells for NK Cells : CD56dim & CD56bright CD56dimconstitutes 90% of peripheral NK cells and these are more cytotoxic than the CD56bright . These cells express higher levels of CD16 than their subset. CD16 is a low-affinity immunoglobulin G (IgG) Fc receptor that is expressed on natural killer (NK) cells. CD56bright cells have the capacity to produce an abundant amount of cytokines. Timmons et al 2006

  12. T-lymphocytes T lymphocytes Migrate to and mature in the thymus. Enter circulation and peripheral lymphoid organs (spleen & lymph nodes) Patrol for invading pathogens and/or tumor cells. Involved in adaptive immunity differentiate further after exposure to an antigen. http://en.wikipedia.org/wiki/Lymphocyte

  13. T-lymphocytes Have a special surface receptor that recognize specific antigens. (Express CD3, and CD8). CD8 cells differentiate into cytotoxic T cells or can be expressed by NK cells. CD3 complex is the complex of α:β or γ:δ T-cell receptor chains. Assist in the recognition and rejection of foreign tissues. CAs, can inhibit lymphocyte proliferation and cytotoxicity. http://en.wikipedia.org/wiki/Lymphocyte

  14. Stress Induced by Exercise Exhaustive Exercise Vigorous physical activity triggers the response of CAs during exhaustive exercise. Know to induce a shift in peripheral blood NK cells. Associated with significant shifts in peripheral immune cell counts. Redistribution of lymphocytes among different compartments of the immune system. Imrich et al 2004, Zhang et al 2006 cache.boston.com/.../swim_06_30/swim13.jpg

  15. The HPA axis and the SNS are activated which induces a release of glucocorticoids and catecholamines which can modulate different aspects in the immune system. Webster-Marketon et al 2008

  16. Hypothesis Exercise-inducedstress: Increases catecholamine levels Decreases natural killer cell cytotoxicity Decreases T-lymphocyte activity.

  17. Overview We will be looking at Plasma concentrations of CAs prior and after vigorous exercise. NK cell and T-lymphocyte cell counts and activity prior and after vigorous exercise. Show the connection of CAs, stress (from exercise), and immune cells.

  18. Experimental Results

  19. NK Cell Count Increase Throughout Training The training group consisted of 15 women in pre-season training for 1 month training for 5h/day. The control group consisted of 7 women instructed to avoid vigorous exercise. Sample of blood from pre-training, during (10th day), end (1day prior to end training, and post-training ( 1 week after). Suzui et al 2004

  20. Concentrations of the CAs and Cytolytic Activity of the NKs Catecholamine levels were not affected. There was no significant difference during the 1 month training process. Nk cell cytolytic activity during and after training. Suzui et al 2004

  21. CAs levels and Cell Counts for Immune Cells The training group consisted of 10 healthy males. 6 weeks of endurance training: 1h run, 4 times a week Followed by 5 days of bed rest. Imrich et al 2004

  22. Flow cytometry Method for quantitating components or structural features of cells & measures fluorescence per cell or particle. Scattered and emitted light from cells and particles are converted to electrical pulses by optical detectors. Parallel light waveforms is picked up by confocal lenses focused at the intersection point of cells and the light source. After the different signals or pulses are amplified they are processed by an Analog to Digital Converter (ADC) which in turn allows for events to be plotted on a graphical scale(One Parameter, Two parameter Histograms). http://biology.berkeley.edu/crl/flow_cytometry_basic.html

  23. CD56dim & CD56brightCell Distribution Dot plot: CD56 and CD3 A total of 10,000 events were collected in the lymphocyte gate based on forward- vs. side-scatter characteristics. N=11 female adolescents age 14 Exercise: Vigorous Cycling Rest: prior to exercise Post: 60 min. after exercise Recovery: 60 min. rest period after exercise. Timmons et al 2006

  24. NK Cell Count and CA Concentrations Epinephrine* P< 0.001 (pg.ml-1) Zhang et al 2006

  25. Effects of Exercise on T-Lymphocytes Subjects consisted of 7 males Exercise: Cycling til’ exhaustion Pre-exercise 60 min Post-exercise 1h post-exercise Trial 1: 6 day Intense Training Period work out everyday. Trial 2: 2 week training, 3-4 sessions per week Trial 3: Same as first trial Lancaster et al 2004

  26. NK cells in Lung Tissue NK cells have different activity in different organs. Kanemi and his team investigated the effect of restraint stress on lung lymphocytes including NK cells. C57BL/6 female mice were exposed to 2 h restraint stress. Kanemi et al 2004

  27. Plasma concentrations of Epinephrine and Norepinephrine N=6 Samples measure by HPLC After the mice were stressed, the CAs levels immediately increased but the value for Norepinephrine was not shown to be significant despite the increase. Con= control RS0= 0 hr RS1= 1 hr RS2= 2 hr Kanemi et al 2004

  28. Stress on pulmonary NK cells Y-axis is the number of cells. Levels of lung NK cells decreased significantly as well as NK cells in the Plasma. Initial decrease occurred during stress and lasted throughout the recovery phase. Immunohistochemical analysis of the lung tissue: a) control mice b) stressed mice. c) NK cells decreased compared to control. Kanemi et al 2004

  29. Conclusion

  30. Summary Supports Hypothesis Suzui et al 2004 NK decrease in cytotoxicity, CAs not affected Imrich et al 2004 CAs increased but Immune cells not affected Increased CAs and decrease NK cell Partial support of Hypothesis Kanemi et al 2006 CAs increased and NK cell increase (cytotoxicity not mentioned) Zhang et al 2006 Increase in CAs, Increase in T-cell (CT not mentioned) Lancaster et al 2004 Refutes Hypothesis CA’s increased in girls,no change in boys; Nk increased in girls, not in boys Timmons et al 2006

  31. Take Home Message Women Exercise decreased cytolytic activity despite an overall increase in NK cells and T-cells. CAs are not affected. Men Immune cells were not affected by exercise but CAs levels increased significantly Adolescents Increase in CAs for girls. Increase in cytolytic activity. Incease in CAs for boys. No significant change in cytolytic activity Mice Stress increased CAs. Decrease in NK cells.

  32. Conclusion According to the data, my hypothesis was partially supported. CAs increase in certain instances as a result of stress from exercise. Cytotoxic activity is not directly mediated by CAs increase. Not enough studies done to show the differences among men, women, adolescents, and rodent models.

  33. Future Experiments Use proper controls. Men: Trained vs. Untrained Women: Trained vs. Untrained Boys: Trained vs. Untrained Girls: Trained vs. Untrained Run a hormone analysis of testosterone, estrogen, and CAs among adolescents and adults after exercise. In vitro experiments to check cytotoxic activity of NK cells and T-cells: Using NK-sensitive and T-sensitive K562 target cell lines and label with non-radioactive europium.

  34. References Benschop, R.J., Nijkamp, F.P., Ballieux, R.E., Heijnen, C. (1994) The effects of B-adrenoreceptor Stimulation on Adhesion of Human Natural Killer Cells to Cultured Endothelium. Br. Journal of Pharmacology113, 1311-1316 Calcagni, E., Elenkov, I. (2006) Stress System Activity, Innate and T Helper Cytokines, and Susceptibility to Immune-Related Diseases. Annual New York Academy of Sciences1069, 62-76 Imrich, R., Tibenska, E., Koska, J., Ksinantova, L., Kvetnansky, R., Bergendiova-Sedlackova, K., Blazicek, P., Vigas, M. (2004) Repeated Stress-Induced Stimulation of Catecholamines Response is not Followed by Altered Immune Cell Redistribution. AnnealsNew York Academy of Sciences1018, 266-272 Kanemi, O., Zhang, X., Sakamoto, Y., Ebina, M,. Nagatomi, R.(2005) Acute Stress Reduces Intraparenchymal Lung Natural Killer Cells Via beta-adrenergic Stimulation. Clinical and Experimental Immunology, 139, 25–34 Lancaster G.I., Halson, S. L., Khan, Q., Drysdale, P., Wallace, F., Jeukendrup, A.E., Drayson, M.T., Gleeson, M. (2004) Effects of Acute Exhaustive Exercise and Chronic Exercise Training on Type 1 and Type 2 T Lymphocytes. Exercise Immunology Rev10, 91-106 Leposavic, G., Pilipovic, I., Radojevic, K., Pesic, V., Perisic, M., Kosec, D. (2008) Catecholamines as Immunomodulators: A role for Adrenoceptor-mediated Mechanisms in Fine Tuning of T-cell Development. Autonomic Neuroscience:Basic and Clinical144, 1-12 Nelson, D.L., Cox, M.M. (2005)Lehninger Principles of Biochemistry. W.H. Freeman and Company. Suzui, M., Kawai, T., Kimura, H., Takeda, K., Yagita, H., Okumura, K., Shek, P.N., Shephard, R.J. (2004) Natural Killer Cell Lytic Activity and CD56dim and CD56bright Cell Distributions During and After Intensive Training. Journal of Applied Physiology96: 2167–2173, 2004 Timmons, B.W., Tarnopolsky, M.A., Bar-Or, O.( 2006) Sex-based effects on the Distribution of NK Cell Subsets in Response to Exercise and Carbohydrate Intake in Adolescents. Journal of Applied Physiology 100, 1513–1519 Webster-Marketon, J.I., Glaser, R. (2008) Stress Hormones and Immune Function. Cellular Immunology252, 16-26 Zhang, X., Matsuo, K., Farmawati, A., Higashi, K. O., Nagata, K., Nagatomi, R. (2006) Exhaustive Exercise Induces Differential Changes in Serum Granulysin and Circulating Number of Natural Killer Cells. Journal of Experimental Medicine210, 117-124 http://en.wikipedia.org/wiki/Adrenergic_receptor http://en.wikipedia.org/wiki/Lymphocyte http:// www.textbookofbacteriology.net http://jem.rupress.org/cgi/content/abstract/190/7/1005 http://www.ott.zynet.co.uk/.../images/encephf1.gif http://users.rcn.com/.../BiologyPages/P/PNS.html http://cache.boston.com/.../swim_06_30/swim13.jpg

  35. Questions/Comments??

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