the role of exercise stress and catecholamines in immunity erika vielmas february 23, 2009 biol 520
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The Role of Exercise Stress and Catecholamines in
Immunity
Erika VielmasFebruary 23, 2009Biol 520
Background Information
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.
http://en.wikipedia.org/wiki/Adrenergic_receptorBenschop et al 1994
Catecholamine Synthesis
OH CH2-CH-COO-
+NH3
TyrosineOH
OH
OH OH
OH OH
CH2-CH2
+NH3
CH-CH2
+NH3
OH
Dopamine
Norepinephrine
CH-CH2
OH
H2N+-CH3
Epinephrine
Nelson & Cox 2005
Dopamine β-Hydroxylase
PhenylethanolamineN-methyltransferase
Tyrosine hydroxylaseAromatic amino acid decarboxylase
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.
Webster-Marketon et al 2008www.ott.zynet.co.uk/.../images/encephf1.gif
PVN
A.P
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 2008users.rcn.com/.../BiologyPages/P/PNS.html
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
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
www.textbookofbacteriology.net
Natural Killer Cells (NK)
Natural Killer Cells are 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.
http://jem.rupress.org/cgi/content/abstract/190/7/1005Calcagni et al 2006Webster-Marketon et al 2008
Two Functionally Distinct Cells for NK Cells : CD56dim & CD56bright
CD56dim constitutes 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
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
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
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 2006cache.boston.com/.../swim_06_30/swim13.jpg
Webster-Marketon et al 2008
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.
Hypothesis
Exercise-induced stress: Increases catecholamine levels Decreases natural killer cell cytotoxicity Decreases T-lymphocyte activity.
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.
Experimental Results
Suzui et al 2004
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).
NK Cell Count Increase Throughout Training
Concentrations of the CAs and Cytolytic Activity of the NKs
Suzui et al 2004
Catecholamine levels were not affected. There was no significant difference during the 1 month training process.
Nk cell cytolytic activity during and after training.
CAs levels and Cell Counts for Immune Cells
Imrich et al 2004
The training group consisted of 10 healthy males.6 weeks of endurance training: 1h run, 4 times a weekFollowed by 5 days of bed rest.
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
CD56dim & CD56bright Cell Distribution
Timmons et al 2006
Dot plot: CD56 and CD3A total of 10,000 events were collected in thelymphocyte gate based on forward- vs. side-scatter characteristics.N=11 female adolescents age 14Exercise: Vigorous CyclingRest: prior to exercisePost: 60 min. after exerciseRecovery: 60 min. rest period after exercise.
NK Cell Count and CA Concentrations
Zhang et al 2006
Epinephrine* P< 0.001
(pg.
ml-1
)
Lancaster et al 2004
Effects of Exercise on T-Lymphocytes
Subjects consisted of 7 malesExercise: Cycling til’ exhaustionPre-exercise60 minPost-exercise1h post-exerciseTrial 1: 6 day Intense Training Period work out everyday.Trial 2: 2 week training, 3-4 sessions per weekTrial 3: Same as first trial
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
Kanemi et al 2004
Plasma concentrations of Epinephrine and Norepinephrine
N=6Samples measure by HPLCAfter the mice were stressed, the CAs levels immediately increased but the value for Norepinephrine was not shown to be significant despite the increase.
Con= controlRS0= 0 hrRS1= 1 hrRS2= 2 hr
Kanemi et al 2004
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.
Stress on pulmonary NK cells
Conclusion
Summary
Supports Hypothesis
Partial support of Hypothesis
Refutes Hypothesis
Suzui et al 2004
Lancaster et al 2004
Imrich et al 2004
Timmons et al 2006
Kanemi et al 2006
Zhang et al 2006
NK decrease in cytotoxicity, CAs not affected
CAs increased but Immune cells not affectedIncreased CAs and decrease NK cell
CA’s increased in girls,no change in boys; Nk increased in girls, not in boys
CAs increased and NK cell increase
(cytotoxicity not mentioned)
Increase in CAs, Increase in T-cell (CT not
mentioned)
Take Home MessageWomen 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 significantlyAdolescents Increase in CAs for girls. Increase in cytolytic activity. Incease in CAs for boys. No significant change in
cytolytic activityMice Stress increased CAs. Decrease in NK cells.
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.
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.
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 Pharmacology 113, 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 Sciences 1069, 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. Anneals New York Academy of Sciences 1018, 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 Rev 10, 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 Clinical 144, 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 Physiology 96: 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 Immunology 252, 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 Medicine 210, 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
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