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Acute Psychological Stress and Exercise and Changes in Peripheral Leukocyte Adhesion Molecule Expression and Density

From the Department of Psychiatry (M.U.G, P.J.M.), University of California, San Diego, La Jolla, CA; and the Department of Medical Psychology (M.U.G.), University of Essen, Essen, Germany.

Address reprint requests to: Marion U. Goebel, MSc, Department of Medical Psychology, University of Essen, Hufelandstrasse 55, D-45122 Essen, Germany. Email: marion.goebel{at}uni-essen.de

	ABSTRACT

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION ACKNOWLEDGMENTS REFERENCES

 
OBJECTIVE: This study examined the effects of acute psychological stress and exhaustive exercise on the expression and density of adhesion molecules (L-selectin, lymphocyte function antigen-1 [LFA-1], and intracellular adhesion molecule-1 [ICAM-1]) on monocytes, granulocytes, and lymphocytes.

METHODS: Forty-five healthy volunteers performed a 15-minute public speaking task and a 15- to 18-minute bicycle ergometer challenge.

RESULTS: In general, both the exercise and speaking tasks led to increases in the number of circulating leukocytes and lymphocyte subsets. The density of L-selectin (CD62L) on mi-ed lymphocytes and T lymphocytes was decreased in response to exercise (p values < .001). Both stressors led to an increased density of LFA-1 (CD11a) on mixed lymphocytes (p values < .01), whereas CD11a density on monocytes and granulocytes remained unchanged. ICAM-1 (CD54) density was unaffected, but the number of lymphocytes, monocytes, and granulocytes expressing CD54 increased in the circulation on both stressors.

CONCLUSIONS: The data indicate that both psychological stress and exercise have significant effects on cellular expression of adhesion molecules on circulating leukocytes. Given the crucial role that adhesion molecules on circulating cells play in inflammation and disease, these findings may have clinical relevance in sympathetic nervous system–induced immune activation.

Key Words: CD62L • CD11a • CD54 • adhesion molecules • stress • exercise.

Abbreviations: CD62L = L-selectin; CD11a = LFA-1; CD54 = ICAM-1; ICAM = intercellular adhesion molecule; LFA = lymphocyte function-associated antigen; NK = natural killer (cell); PE = phycoerythrin; SNS = sympathetic nervous system; VO_2max = maximum oxygen consumption.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION ACKNOWLEDGMENTS REFERENCES

 
Leukocytosis, an increase of leukocytes in the circulation in response to acute psychological stress or short-term intensive exercise, is a well-documented phenomenon (1). Yet the underlying mechanism of altered lymphocyte trafficking on acute activation of the SNS has not been fully revealed. Previous studies in this field have focused on the relation among catecholamines, adrenoreceptor mechanisms, and altered leukocyte trafficking (2–4). There is growing evidence that cellular adhesion molecules are also altered after acute activation of the SNS and might therefore contribute to stress-induced leukocytosis (5).

Adhesion molecules expressed on the cell surface of both the leukocyte and the endothelial wall have a pivotal role in leukocyte trafficking (6, 7). CD62L is expressed on most circulating leukocytes and mediates leukocyte rolling and regulates the homing of naive lymphocytes to secondary lymphoid tissues (8). CD11a is expressed on all leukocytes and exists in either a low- or high-affinity state. In response to activating signals, CD11a is upregulated to the high-affinity state, a process that likely involves aggregation on the cell surface and changes in conformation (9). Once activated, CD11a binds tightly to its ligands (ICAM-1, ICAM-2, or ICAM-3) on the endothelium, and this is generally followed by leukocyte transendothelial migration (9).

Kurokawa et al. (10) reported a greater increase of CD8⁺ lymphocytes with high expression of CD11a (CD8⁺CD11a^high+) compared with low expression of CD11a (CD8⁺CD11a^low+), as well as a preferential increase of CD62L^- but not CD62L⁺ T cells after intensive exercise. More recent studies confirm that a certain pattern of adhesion molecule expression is involved in the differential mobilization of lymphocyte subsets on exercise (11, 12). Moreover, prior treatment with the nonselective ß-blocker propranolol attenuates the increase of CD62L^- T lymphocytes on exercise, showing the coregulatory function of ß₂-adrenergic mechanisms in the redistribution of CD62L^- T cells (13).

Still it is unclear whether these findings are due to a loss (shedding) of CD62L, an influx of CD62L^- cells, an efflux of CD62L⁺ cells, or a combination of these factors. Studies examining soluble adhesion molecules such as E-selectin (CD62E) and ICAM-1 support the possibility of shedding on exercise (14, 15). On the other hand, activated lymphocytes and a subpopulation of memory T cells express lower levels of CD62L, suggesting a distinct recruitment of these cells after activation of the SNS (16, 17). In addition, exercise has been found to preferentially mobilize cells with higher CD11a expression (18).

Regarding the question of the origins of the invading cells, it is likely that during exercise leukocytes are mobilized from the marginal pools of blood vessels (19). Catecholamines probably reduce the adhesiveness, and together with an increase in blood velocity, leukocytes are detached into circulation (1, 19). Also, the spleen is thought to promote the leukocytosis because Nielsen (2) demonstrated that the spleen provides two-thirds of invading lymphocytes during exercise.

In contrast to exercise, little attention has been paid to the effects of acute psychological stress on adhesion molecules (20). Lymphocyte redistribution after an acute psychological stressor generally seems to follow a similar mechanism as exercise, with accompanying increases in epinephrine and norepinephrine (21). Using the chronic stress model of Alzheimer’s caregivers, we recently observed lower CD62L expression on T lymphocytes of stressed caregivers as compared with control subjects (22). However, the physiological meaning of downregulation of CD62L is unclear. Although we know little about the changes of adhesion molecule expression and its impact on leukocyte trafficking in the different contexts of acute and chronic stress (23, 24), the clinical application for inflammatory diseases or transplantation is apparent (25, 26). Interestingly, altered adhesion molecule expression is thought to have an impact during myocardial infarction (27).

Few, if any, studies have investigated and compared the differential effects of acute psychological stress and exercise on the expression of adhesion molecules. Therefore, we examined and compared and contrasted the effects of a standardized speaking task and an exercise task on adhesion molecules. To facilitate comparison of our data to data from existing exercise studies, we studied L-selectin, ICAM-1, and LFA-1. We quantified adhesion molecule expression and density on lymphocytes, monocytes, and granulocytes.

	METHODS

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Subjects
Forty-five healthy volunteers (mean age = 36 years, SD = 7 years) were studied after they provided written informed consent. All subjects provided a history and underwent physical examination (performed by a physician) and were identified as healthy. All underwent electrocardiography to ensure that there were no cardiac abnormalities before participation, and only those with normal results on their electrocardiogram were studied. Volunteers were recruited from the local community and were paid for their participation. The protocol was approved by the institutional review board of the University of California, San Diego.

Procedures
All subjects were studied at the UCSD Medical Center General Clinical Research Center between 8:15 AM and 12:00 PM. Subjects refrained from consuming caffeinated beverages and smoking for 12 hours before study. On arrival at the laboratory, subjects were seated, a 19-gauge catheter was inserted into a forearm vein, and then they rested for 30 minutes. Starting at 9:00 AM, in a fixed order, volunteers performed a 15-minute speaking task and a 15- to 18-minute bicycle ergometer exercise. There was a 60-minute period between completion of each task and the start (baseline) of the next task. The speaking task consisted of two back-to-back speeches. While seated, the subject prepared (3 minutes/speech) and then presented a speech (3 minutes/speech) on a hypothetical situation. The total time of the speaking task, including the 6 minutes of preparation, the 6 minutes of presentation, and instruction, was approximately 15 minutes. Subjects were told that the speech would be evaluated and rated by experts. The two speeches involved defending oneself from being falsely accused of shoplifting and a confrontation with an unscrupulous car dealer. If subjects stopped speaking before the time was up, they were reminded to continue talking by reiterating and summarizing their points (28).

For the exercise task, subjects were informed that the exercise itself would last 15 to 18 minutes, beginning with a series of 3-minute stages marked by increasing resistance and thus greater effort on their part. They were told that the peak level of effort would be challenging and that once that peak had been established the workload would actually be slightly reduced for the remainder of the exercise period. They were informed of warning signs of excess exertion (eg, faintness, shortness of breath, dizziness, and muscle cramps) and that although such complications were not expected, they should inform the investigator immediately if any occurred. Subjects were instructed to begin pedaling and to achieve and maintain a pedal rate of 70 rpm as indicated on the ergometer display panel in their view. VO_2max was estimated using heart rate, and workload was adjusted so that the exercise was completed at a level comparable to 75% of estimated VO_2max for each subject. After the test, wheel resistance was removed, and subjects continued to pedal freely against no resistance for 5 minutes (cooldown period).

Leukocyte Subsets
Whole blood was sampled before, immediately after, and 15 minutes after each challenge. Blood was preserved with ethylenediaminetetraacetic acid and maintained at room temperature (23°C). Complete blood count was analyzed by using a Coulter STKS CBC Counter. Flow cytometry (FACSCalibur, Becton Dickinson, San Jose, CA) using CellQuest software was used to quantify lymphocyte, monocyte, and granulocyte populations and adhesion molecules (29). Blood was processed within 3 hours of collection and was stained with monoclonal antibodies conjugated to various fluorochromes. The lysing reagent was FACS Brand Lysing Solution (Becton-Dickinson), which results in simultaneous lysis of red blood cells and partial fixation of leukocytes. Positive four-color staining was used with monoclonal antibodies conjugated to either fluorescein isothiocyanate, PE, peridinin chlorophyll protein, or allophycocyanin (Becton-Dickinson and PharMingen, San Jose, CA). Fluorescence compensation was performed using CaliBRITE beads (Becton-Dickinson) and FACSComp software. Optimal amounts of antibodies were used and 8000 to 15,000 events were analyzed per tube. Isotypic controls were used for each assay to determine nonspecific staining. Phenotypes were expressed as the percentages of total cells analyzed by flow cytometry. Gating strategies for multiparameter analyses were performed using side scatter vs. FL3 (peridinin chlorophyll protein) (CD8⁺ cells) or side scatter vs. FL4 (allophycocyanin) (CD4⁺ cells) using various combinations of monoclonal antibodies. For quantification of adhesion molecule density, the number of antibodies bound per cell was estimated using flow cytometry with Quantibrite PE beads (Becton-Dickinson). The Quantibrite PE beads were run using the same instrument settings as used for the assay. The number of PE molecules per bead was calibrated with the geometric mean of the bead peaks in linear fluorescence, and the FL2 (PE) axis was converted into the number of PE molecules bound per cell. The number of antibodies that bind to the specific cell provides a good approximation of antigen density.

To measure catecholamines, blood was collected on ice before and immediately after the speech and exercise tasks and separated in a refrigerated centrifuge. The plasma was stored at -80°C until assay. Epinephrine and norepinephrine were determined by radioenzymatic assay (30). The intra- and interassay coefficients of variation for the assay are 6.5% and 11%, respectively. We gathered complete catecholamine data on 43 of the 45 subjects.

Statistical Analysis
Data were analyzed using one-factor (time) repeated-measures analysis of variance (SPSS statistical software, version 9.0). For multiple comparisons, Bonferroni adjustment was performed.

	RESULTS

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The tasks induced significant SNS activation, indicated by increased circulating catecholamine levels. The speech task induced a significant increase in levels of plasma norepinephrine (from 300 pg/ml (SD ± 123) at rest to 335 pg/ml (SD ± 130) after the speech, F(1,42) = 10.9, p = .002) and epinephrine (from 40 pg/ml (SD ± 37) at rest to 70 pg/ml (SD ± 144) after the speech, F(1,42) = 3.5, p < .05). Exercise induced a significant increase in levels of plasma norepinephrine (from 404 pg/ml (SD ± 172) at rest to 722 pg/ml (SD ± 342) after exercise, F(1,42) = 49, p < .001) and epinephrine (from 52 pg/ml (SD ± 32) at rest to 99 pg/ml (SD ± 94) after exercise, F(1,42) = 12, p = .001).

Leukocyte Subsets and Adhesion Molecule Expression
The data for lymphocytes, monocytes, and granulocytes are presented in Table 1. The speech task led to increases in circulating levels of mixed (B, T, and NK cells) lymphocytes (F(1,44) = 9.27, p < .001), monocytes (F(1,44) = 5.93, p = .004), CD8⁺ T cells (F(1,44) = 10.07, p < .001), CD3^-CD16⁺56⁺ NK cells (F(1,44) = 20.158, p < .001), granulocytes (F(1,44) = 4.237, p = .018), and CD4⁺ T cells (F(1,44) = 4.60, p = .013).

Subsets not expressing CD62L, such as CD8⁺CD62L^- (F(1,44) = 37.7, p < .001), CD4⁺CD62L^- (F(1,44) = 23.3, p < .001), and CD3^-CD16⁺56⁺CD62L^- (F(1,44) = 12.3, p < .001), were elevated on exercise (Table 2). Moreover, circulating levels of cells expressing CD62L, such as CD8⁺CD62L⁺ (F(1,44) = 32.12, p < .001), CD4⁺CD62L+ (F(1,44) = 49.79, p < .001), and CD3^-CD16⁺56⁺CD62L⁺ (F(1,44) = 38, p < .001), were also elevated. In addition, the numbers of lymphocytes (F(1,44) = 74.87, p < .001), monocytes (F(1,44) = 26.34, p < .001), and granulocytes (F(1,44) = 18.61, p< .001) expressing CD54 were increased.

Leukocyte Subsets and Adhesion Molecule Density
Adhesion molecule density varied among lymphocyte subsets ( Table 3). The surface density of CD62L only slightly and nonsignificantly decreased on lymphocyte subsets on the speech task (Table 3 and Fig. 1). In contrast, on exercise, the density of CD62L was significantly lower than the baseline level before exercise on mixed lymphocytes (F(1,44) = 20.14, p < .001), CD8⁺ cells (F(1,44) = 24.62, p < .001), and CD4⁺ cells (F(1,44) = 7.85, p = .001) and returned near baseline levels during the recovery phase (Table 3 and Fig. 1).

View larger version (21K): [in this window] [in a new window]   Fig. 1. L-selectin (CD62L) density (number of PE molecules bound per cell) in response to a speaking and an exercise task. In response to public speaking (top), the surface density of CD62L was decreased, but not significantly, on mixed lymphocytes, CD8+ cytotoxic cells, and CD4+ helper T cells. In response to exercise (bottom), the surface density of CD62L was significantly decreased on mixed lymphocytes, CD8+ cytotoxic cells, and CD4+ helper T cells (p values < .001).

View larger version (17K): [in this window] [in a new window]   Fig. 2. LFA-1 (CD11a) density (number of PE molecules bound per cell) on lymphocytes in response to speaking and exercise tasks. The surface density of CD11a on lymphocytes was greater after both the exercise (p < .001) and speaking (p < .01) tasks.

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION ACKNOWLEDGMENTS REFERENCES

 
This study examined the effects of psychological stress and exercise on leukocytes and lymphocyte subsets and their differential changes according to adhesion molecule expression. We replicated the existing findings of leukocytosis after such stressors as a speaking task and exercise (1), because exercise and psychological stress resulted in a marked elevation in all leukocyte and lymphocyte subsets. The exercise task, however, had more prominent effects than the speaking task, which is consistent with the larger catecholamine increase in response to exercise (31).

After exercise, the surface density of CD62L was decreased on mixed lymphocytes and CD4⁺ and CD8⁺ T cells; CD62L density returned to near baseline levels 15 minutes later. Because we did not assess levels of soluble CD62L in the circulation, we cannot exclude the possibility of shedding, which is a limitation of our study. There is mixed evidence on the effects of SNS activation on levels of soluble adhesion molecules. There is some evidence of CD62L shedding due to exercise (14), but some studies show an exercise-induced increase of soluble ICAM-1 levels (15, 32). Other studies show no change in levels of soluble ICAM-1, soluble CD62L, or soluble CD62E (E-selectin) after infusion of adrenergic agonists (5, 33). In this study, ICAM-1 density did not significantly change on lymphocytes, monocytes, or granulocytes. However, the absolute numbers of CD54⁺ lymphocytes and monocytes, but not granulocytes, increased. In contrast to previous findings (10, 13), both CD62L^- and CD62L⁺ T lymphocytes increased after the speaking task and exercise, although the relative increase was more marked for CD62L^- cells. Kurokawa et al. (10), however, used a 60-minute bicycle exercise task with blood first drawn 30 minutes into exercise, which may explain the variations in the findings.

Lymphocyte CD11a density was higher after the speech and exercise tasks. The fact that lymphocyte CD62L density was decreased and lymphocyte CD11a density was simultaneously increased is likely due, at least in part, to redistribution of the lymphocyte subsets. We have previously shown that infusion of isoproterenol (a ß-agonist) preferentially mobilizes T cells of the memory/activated phenotype, whereas propranolol (a ß-blocker) diminishes these effects (33). In general, naive lymphocytes (CD45RA⁺CD45RO^-) are mostly CD62L^high+ cells and lose the CD62L expression on encounter with antigen, whereas memory T cells (CD45RA^-CD45RO⁺) show low CD62L expression and increased density of CD11a (16). On activation of T cells, CD62L is downregulated with a decrease of 90% within the first 4 hours of activation in vitro (34). Therefore, activated and naive T cells can be distinguished by their surface adhesion molecule expression. However, memory and effector T cells share the same pattern of surface markers, including CD62L (35, 36). We hypothesize that differences in homing and migration of the activated/memory phenotype contribute to the stress-induced change in CD62L and CD11a expression. Memory T cells might be retained to a larger amount in the spleen than in the lymph nodes (16) and provide the ability for a fast mobilization of already activated lymphocytes in conditions such as acute activation of the SNS.

The data extend earlier findings on exercise and adhesion molecule expression (37, 38), showing that the phenotypic characteristics of circulating cells after exercise are similar to those that invade on exposure to an acute psychological stressor. In general, the psychological stressor led to a somewhat similar profile of expression of adhesion molecules as compared with exercise. Both stimuli led to greater expression of CD11a on circulating lymphocytes. These parallel findings in the profile of CD11a and in part of CD62L expression resulting from exercise and psychological stress may be related to activation of the immune system in the sense of a fight-flight response. Besides cells of the nonspecific immune response (eg, NK cells) entering into circulation, T lymphocytes that have already seen antigen emerge.

Recent studies suggest that the chronic psychological stress of caregiving and burnout at the workplace affect adhesion molecule expression and leukocyte adhesiveness (22, 39). Caregiving and burnout are also associated with immunologic decrements and increased cardiovascular disease (22, 39–41). Given the important effect of adhesion molecules on circulating cells in the inflammation response, including atherosclerotic processes (25–27), one can speculate that stress-mediated effects on adhesion molecules may have clinical relevance.

	ACKNOWLEDGMENTS

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The authors are grateful to Michael G. Ziegler, MD, for analyzing the catecholamines and to Jose Loredo, MD, for obtaining the histories and performing the physical examinations. In addition, we are grateful to the Immunogenetics Laboratory at the Veterans Affairs Medical Center for leukocyte determinations. This work was supported by Grants MO1-RR00827, HL-57265, and AG-13332 from the National Institutes of Health.

Received for publication June 21, 1999.

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TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION ACKNOWLEDGMENTS REFERENCES

 

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