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Psychosomatic Medicine 63:493-501 (2001)
© 2001 American Psychosomatic Society

ORIGINAL ARTICLES

Heart Rate, Neuroendocrine, and Immunological Reactivity in Response to an Acute Laboratory Stressor

Mark R. Larson, PhD, Robert Ader, PhD and Jan A. Moynihan, PhD

From the Center for Psychoneuroimmunology Research, University of Rochester Medical Center, Rochester, New York.

Address reprint requests to: Mark R. Larson, PhD, The Center for PNI Research, Department of Psychiatry, Box PSYCH, University of Rochester Medical Center, 300 Crittenden Blvd., Rochester, NY 14642. Email: Mark_Larson{at}urmc.rochester.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
 ACKNOWLEDGMENTS
 REFERENCES
 
OBJECTIVE: The primary objective of the present study was to identify neuroendocrine and immunological correlates of cardiovascular reactivity to an acute laboratory stressor.

METHODS: Subjects were 56 healthy volunteers. Heart rate and blood pressure were assessed at regular intervals during a 30-minute adaptation period and a 6-minute videotaped speech task. Blood was drawn before and after the task and was assayed for natural killer cell activity (NKCA), cortisol production, in vitro interferon gamma (IFN-{gamma}) and interleukin 10 production by peripheral blood mononuclear cells (PBMC), and antibody titers to the Epstein-Barr virus. Psychological measures were also administered.

RESULTS: NKCA increased significantly in response to the task, and this increase was significantly and positively correlated with heart rate reactivity. IFN-{gamma} production by PBMC also increased in response to the task, but these increases were unrelated to heart rate reactivity. In addition, baseline cortisol levels were found to be predictive of heart rate reactivity. Finally, questionnaire data were modestly related to various aspects of stress-induced reactivity.

CONCLUSIONS: Consistent with the task-related increases in NKCA and IFN-{gamma}, acute stress may signal an increase in at least some aspects of the cell-mediated, or TH1-driven, immune response. Furthermore, the finding that heart rate reactivity was related in part to baseline individual differences in cortisol production suggests that short-term cardiovascular responses to stress may be directly related to longer-term neuroendocrine modulation. Finally, the present results also help to highlight the influence of both sympathetic and nonsympathetic pathways in the response to acute stressors and suggest tentative links between certain psychological traits and various aspects of stress-induced reactivity.

Key Words: cardiovascular reactivity • natural killer cells • cytokines • cortisol • Epstein-Barr virus • psychoneuroimmunology.

Abbreviations: ANCOVA = analysis of covariance; AXS = Anger Expression Scale; DBP = diastolic blood pressure; EBV = Epstein-Barr virus; HR = heart rate; IFN-{gamma} = interferon gamma; IL = interleukin; MCSDS = Marlowe-Crowne Social Desirability Scale; MMPI = Minnesota Multiphasic Personality Inventory; NKCA = natural killer cell activity; PBMC = peripheral blood mononuclear cells; SBP = systolic blood pressure; SNS = sympathetic nervous system; TH = T helper (cell); TMAS = Taylor Manifest Anxiety Scale; TNF = tumor necrosis factor.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 NOTES
 ACKNOWLEDGMENTS
 REFERENCES
 
In recent years, researchers have become increasingly interested in examining the impact of stress on the neuroendocrine and immune systems. Brief laboratory stressors, such as mental arithmetic and public speaking tasks, have been found to induce reliable shifts in a number of physiological parameters, including significant increases in NKCA (1–3). Interestingly, these increases seem to be potentiated in individuals who are most cardiovascularly reactive to stress (4–7). In other words, those individuals who show the greatest SNS response to brief psychological stressors also have increased endocrine and immune system alterations in response to the same stressors. This has led some researchers to suggest that SNS reactivity might mediate, or serve as a biological marker of, at least some aspects of neuroendocrine and immune system responsivity (8, 9).

In addition to cortisol production and NKCA, recent studies indicate that cytokine production also varies in an organized manner in response to stress (10–12). CD4+ TH cells may be subdivided into TH1 and TH2 subsets, which are defined by the cytokines they produce when stimulated by antigen. TH1 cells produce IFN-{gamma}, TNF, and IL-2, which elicit macrophage activation and are crucial for cell-mediated immunity (eg, delayed-type hypersensitivity reactions). TH2 cells produce IL-4, IL-5, IL-10, and IL-13, which encourage strong antibody responses (10, 13–15). Despite indications that chronic stress may induce humoral (TH2) immune responses to predominate over cell-mediated (TH1) immune responses (11, 12, 16), preliminary evidence suggests that the cytokine response to acute stress may actually be characterized by the opposite pattern (10). Specifically, the production of IFN-{gamma}, a TH1 cytokine produced by T cells and NK cells, was shown to increase in response to acute stress. Meanwhile, the production of IL-4, a TH2 cytokine, did not increase. Because SNS reactivity has been linked to increased NKCA and alterations of various peripheral blood lymphocyte populations (17–19), both of which may in turn influence cytokine production, it seems plausible that these stress-induced cytokine alterations may also be related to SNS reactivity. This hypothesis, however, has not been explored.

In the present study, we examined stress-related changes in NKCA and cortisol, IFN-{gamma}, and IL-10 production using a brief laboratory stressor. In addition, we attempted to determine whether these changes might be predictably related to HR reactivity in response to the same task. We hypothesized that the task would increase cortisol and IFN-{gamma} production and NKCA. Based on the apparent links between SNS reactivity, NKCA, and cytokine production, we also hypothesized that those individuals who were most reactive to acute stress (ie, high HR reactors) would exhibit a greater increase in NKCA and IFN-{gamma} production in response to the task than individuals who were less reactive to the same stressor (low HR reactors).

Less well established than the link between SNS reactivity and endocrine and immune system activation is the biological relevance of these acute stress responses. Acute laboratory stressors typically last for a matter of minutes, and shifts in specific endocrine and immune responses to these brief stressors generally dissipate within an hour of completion of the stressful task. Although it has been speculated that those who are high SNS reactors might evidence longer-term endocrine or immune system modulation (7, 9, 20), high sympathetic reactivity in the laboratory has yet to be definitively linked to stable immune or endocrine differences across individuals. This was, therefore, a second purpose of the present study. In particular, we explored baseline cortisol, IFN-{gamma} and IL-10 production, as well as baseline NKCA, to determine whether any of these variables might systematically covary with HR reactivity (which served as a rough estimate of SNS activity).

In addition to these variables, we also assessed the relationship between HR reactivity and antibody titers to EBV. Approximately 90% of the adult population has previously been infected with EBV, a human herpesvirus that results in latent infection for the life of the individual (21). If the virus is reactivated because of either biological or psychosocial influences, viral antigens are expressed, an immune response is triggered, and anti-EBV antibodies are produced. Increased anti-EBV antibody production has been found to consistently and significantly correlate with chronic psychological stressors such as academic stress (22) and divorce (23) and is thought to reflect the immune system’s ability (or inability) to keep the virus under control (24).

Finally, a secondary aim of the present study was to examine several psychosocial factors that are reportedly related to both stress-induced cardiovascular reactivity and immune function. Specifically, questionnaires were used to assess the so-called "traits" of anger expression (25), cynical hostility (26), defensiveness (27), and manifest anxiety (28). Based on previous research, it was expected that heightened cardiovascular reactivity would be related to anger expression (29), cynical hostility (30), and defensiveness (30, 31) and that manifest anxiety scores would be positively correlated with EBV antibody titers (32). In addition, frequently occurring minor stressors, or "hassles" (33), were assessed because they have previously been shown to be related to health status (34) and to at least one aspect of immune function (35).


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 NOTES
 ACKNOWLEDGMENTS
 REFERENCES
 
Subjects
Fifty-six subjects (19 men and 37 women) aged 18 to 59 years (mean = 28.3 years, SEM = 1.12) participated in this study. All were tested in the Clinical Research Center at the University of Rochester Medical Center in late spring/early summer (between the dates of May 5 and July 10). No recruitment restrictions were made in terms of racial or ethnic origin. The sample was 70% white, 16% Asian, 7% African American, and 7% Hispanic; these percentages were evenly distributed across genders. All subjects were volunteers recruited through advertisements posted at the University of Rochester Medical Center. Eligibility was determined using a standard telephone screening procedure. Subjects were excluded from the study if they reported 1) a history of chronic illness, 2) hypertension, 3) weight 20% or more above or below ideal body weight (based on height), 4) regular use of tobacco products, 5) consumption of more than 10 alcoholic beverages weekly, 6) speech or needle phobias, or 7) use of illicit or prescription medications (except oral contraceptive use, which was reported by eight women). All but one woman was premenopausal. Although the present study did not control for menstrual phase, these data were collected to verify that menstrual phase was randomly distributed across female subjects. All subjects were tested in the morning (at either 8:30 or 10:30 AM) and were instructed to fast (ie, drink only water) and to abstain from caffeine use and strenuous exercise beginning at midnight the previous evening. In addition, subjects were asked to abstain from ingesting alcohol and over-the-counter medications during the 24-hour period preceding the experiment, and they were asked to reschedule the appointment if they felt ill at the time of the experiment. All subjects provided written informed consent and were paid $30 for their participation.

Procedure
After experimental procedures were explained and informed consent obtained, each subject completed a health-related screening questionnaire, and measurements of height and weight were obtained. Next, an intravenous catheter was inserted into the antecubital vein of the subject’s dominant arm by a trained phlebotomist for collection of blood samples, and an occluding cuff was placed on the nondominant arm for measurement of HR, SBP, and DBP (Dinamap 930x, Critikon, Tampa, FL). Subjects were then asked to sit quietly for a 30-minute adaptation period. For adaptational purposes, HR, SBP, and DBP were assessed at 2-minute intervals during the first 24 minutes of this period and at 1-minute intervals thereafter for the remainder of the adaptation period (minutes 25–30). These last 6 minutes of the adaptation period were averaged and used as baseline values. Immediately after the 30-minute adaptation period, a 40-ml blood sample was obtained. All subjects were then asked to perform a simulated public speaking task, which was based on the Stress Inducing Speech Task (36, 37). This task involved 2 minutes of speech preparation, followed by 4 minutes of videotaped speech delivery. For the speech task, subjects were asked to describe their own best and worst personal characteristics. In addition, subjects were asked to be as persuasive as possible in their speech delivery, because their speeches would be videotaped for later analysis by a group of psychologists who would rate each speech against all other participants’ speeches for persuasiveness. The 6-minute length of the task was chosen to be consistent with the length of other similar public speaking tasks (eg, see Refs. 4 and 7). HR, SBP, and DBP were assessed at 1-minute intervals throughout the 6-minute task, and a second 40-ml blood sample was obtained immediately after completion of the task. Cardiovascular data obtained during the 4 minutes of speech delivery were first analyzed to verify that results did not significantly differ as a function of task minute. Because no significant differences were found, these data were then averaged and recorded as task values. The experiment concluded with a battery of self-report questionnaires and subject debriefing. This experiment received the full approval of the Research Subjects Review Board at the University of Rochester Medical Center.

Endocrine and Immune Assays
Plasma cortisol levels were assayed by standard radioimmunoassay techniques using a kit (ICN Biomedicals, Orangeburg, NY). Briefly, plasma samples were diluted 1:250 and combined with the appropriate cortisol antiserum. Bound cortisol was then marked with a radioactive tracer (3H) and counted in a beta counter (LKB-WALLAC, Turku, Finland). Resultant values were compared against a standard curve to determine plasma cortisol levels (in ng/ml).

PBMC were isolated from 30 ml of diluted, heparinized blood by centrifugation over Ficoll-Hypaque (Pharmacia, Piscataway, NJ). PBMC at the interface were washed twice, counted, and resuspended to a concentration of 5 to 10 x 106 cells/ml in fetal bovine serum. Cells were frozen at -80°C according to the protocol of Vingerhoets et al. (38). At the time of assay, aliquots of thawed cells were washed twice and resuspended to a concentration of 107 cells/ml in RPMI-1640 medium containing 10% fetal bovine serum, 2 mM L-glutamine, 50 mM 2-mercaptoethanol, 25 mM HEPES, 100 U/ml penicillin, and 100 mg/ml streptomycin sulfate (complete RPMI, all reagents from Gibco, Grand Island, NY).

A standard 51Cr-release assay using the K562 cell line (American Type Culture Collection, Rockville, MD) as the target was used to measure NK cell activity (39). Effector cells were mixed in complete RPMI with 51Cr-labeled target cells at effector-to-target (E:T) cell ratios of 100:1, 50:1, 25:1, and 12.5:1. Supernatants were harvested after a 6-hour incubation in 5% CO2 at 37°C and counted in a gamma counter (WALLAC Oy, Turku, Finland). Statistical analyses were conducted to determine the percentage of specific lysis for all four E:T ratios. Regression analysis confirmed that data from all four E:T ratios followed a linear progression at both time points (r = 0.99). As a result, percentage of lysis values were standardized arbitrarily at the 50:1 dilution so that individual values could be compared across time points for all participants.

Cytokine production was assessed using PBMC at 5 x 106 cells/ml, which were cultured with 1 or 10 µg/ml of monoclonal anti-CD3 antibody (PharMingen, San Diego, CA) in complete medium. Supernatants were harvested at 48 and 72 hours and assayed for IFN-{gamma} and IL-10 using a standard enzyme-linked immunosorbent assay protocol and anti-cytokine antibody pairs (PharMingen) (40–42). These assays have a reliability of greater than 90%.

Finally, serum was analyzed for immunoglobulin G antibody to EBV nuclear antigen by enzyme-linked immunosorbent assay using reagents supplied as a kit (Incstar, Stillwater, MN). Samples were diluted 1:101, added to precoated 96-well plates (100 µl/well), and incubated for 60 minutes at 37°C. Plates were then washed four times with phosphate-buffered saline containing Tween-20. Next, affinity-purified goat anti-human immunoglobulin G conjugate was added (100 µl/well), and plates were incubated for 1 hour at 37°C. Plates were again decanted, blotted, and washed, and a chromogen/substrate solution was added (100 µl/well). Finally, plates were incubated for 30 minutes at room temperature; absorbance was measured at 450 nm.

Psychological Instruments

1. The Cook-Medley Hostility Inventory (26) consists of 50 true/false items derived from the MMPI (43). The scale has adequate internal consistency (26), test-retest reliability (44), and construct validity (45), assessing primarily suspiciousness, resentment, and cynical mistrust. For the present study, the CHOST score (46) was used in place of the overall Cook-Medley score because it is thought to more accurately tap the dimension of hostility and to more strongly correlate with HR reactivity (47) than does the overall score.
2. Spielberger’s 20-item AXS (25) assesses self-reported anger and yields three scores: anger expressed toward others or the environment (anger-out), anger that is "suppressed" or expressed toward the ego or the self (anger-in), and a total anger expression score (anger-total). The psychometric properties of the AXS are well established (25, 48).
3. The MCSDS (27) is a 33-item questionnaire that is thought to measure defensiveness, protection of self-esteem, and affect inhibition (31). It also has adequate internal consistency and test-retest reliability (27).
4. The TMAS (28), also derived from the MMPI (43), is a questionnaire that was designed to assess typical or chronic anxiety reactions (28, 32). Its validity and test-retest reliability are adequate (28), and for the present study the 20-item TMAS short form (49) was used.
5. Finally, the Hassles Scale (33) is a frequently used measure of minor daily stressors (hassles). Of the 53 items contained in the revised Hassles Scale (34), three were eliminated because of their redundancy with our original screening criteria (questions about smoking, alcohol use, and mood-altering drug use). The remaining 50 items were scored from 0 ("none" or "not applicable") to 3 ("a great deal"), and total hassles scores were obtained by summing across ratings.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 NOTES
 ACKNOWLEDGMENTS
 REFERENCES
 
Responses to the Speech Task
Cardiovascular data.
Repeated-measures ANCOVAs were used to examine task-related changes in HR, SBP, and DBP. Factors included period (baseline vs. task) and gender (male vs. female). Period was the repeated-measures factor, and age served as a covariate in all analyses. In addition, because cortisol values tend to vary greatly over the course of a morning, analysis of task-related cortisol changes included time of day (8:30 vs. 10:30) as an additional between-subjects factor in this and all subsequent analyses. Results revealed that the speech task significantly increased HR (F = 163.3; df = 1,54; p < .0001), SBP (F = 142.1; df = 1,54; p < .0001), and DBP (F = 57.3; df = 1,54; p < .0001). Consistent with previous research (50–52), HR was significantly higher for women than for men (F = 5.0; df = 1,53; p < .03), whereas SBP and DBP were generally higher for men than for women (SBP: F = 10.7; df = 1,53; p < .002; DBP: F = 12.3; df = 1,53; p < .001). No significant main effects for age or time of day were noted, and no interactions were significant. Means and standard deviations for these variables by gender are found in Table 1.


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  		Table 1. Mean Baseline and Task Values for HR, SBP, and DBP by Gender a
 
Neuroendocrine and immune data.
Similar repeated-measures ANCOVAs were used to compare data obtained from pre- and posttask blood draws. NKCA was found to increase significantly in response to the task (F = 34.0; df = 1,51; p < .0001), as did IFN-{gamma} production by PBMC (F = 7.5; df = 1,52; p < .009). Ninety-one percent of subjects (48 of 53) actually showed increased NKCA in response to the task, whereas 69% of subjects (37 of 54) showed increased IFN-{gamma} production. In contrast, neither the production of cortisol nor IL-10 changed significantly in response to the task. Means and standard deviations for these variables are found in Table 2. No main effects for age, gender, or time of day were significant at the p < .05 level, and no significant interactions were noted.


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  		Table 2. Mean Baseline and Task Values for NKCA, Cortisol Production, IFN-{gamma} Production, and IL-10 Productiona
 
Relationship of Neuroendocrine and Immune Reactivity to HR Reactivity
Forward stepwise regression analyses were used to compare task-related changes in NKCA, IFN-{gamma}, IL-10, and cortisol to task-related HR reactivity. Change scores for all variables were quantified as task minus baseline values. Gender and age served as steps 1 and 2 in these analyses, and HR reactivity was step 3. As with the ANCOVAs, an extra step representing time of day (8:30 vs. 10:30) was added for all analyses involving cortisol (added before HR reactivity). Changes in NKCA were found to be significantly and positively correlated with HR reactivity (df = 1,51; r = 0.40, p < .004; Figure 1). In contrast, IFN-{gamma}, IL-10, and cortisol reactivity were all unrelated to HR reactivity. No significant effects were noted for age, gender, or time of day.



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  		Fig. 1. Scatterplot of baseline to task increases in NKCA (% lysis) vs. HR reactivity (beats/min). The line is plotted by linear regression (r = 0.40, p < .005).

 
Relationship of Baseline Data to HR Reactivity
Similar stepwise regression analyses were used to determine whether HR reactivity was significantly correlated with baseline levels of cortisol, NKCA, IFN-{gamma}, IL-10, and EBV antibody titers. Both age (df = 1,52; partial correlation = -0.33; p < .02) and HR reactivity (df = 1,52; partial correlation = 0.29; p < .04; Figure 2) were found to be significantly correlated with baseline cortisol levels, although in opposite directions. The combined model using both age and HR reactivity accounted for 18.4% of the variance associated with baseline cortisol levels (df = 2,52; multiple r = 0.43; p < .005). Meanwhile, HR reactivity was not found to be significantly related to baseline NKCA, IFN-{gamma}, IL-10, or EBV antibody titers (all p values > .05), nor were any other significant effects noted for age, gender, or time of day.



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  		Fig. 2. Scatterplot of baseline cortisol levels (ng/ml) vs. HR reactivity (beats/min). The line is plotted by linear regression (partial correlation = 0.29, p < .04).

 
Psychological Measures
Similar stepwise regression procedures were used to relate the five psychological measures with HR, immune, and neuroendocrine reactivity as well as with antibody titers to EBV. These analyses yielded largely nonsignificant findings. However, there were two exceptions to this general rule. First, TMAS scores were significantly and negatively correlated with HR reactivity (df = 1,54; r = -0.32; p < .02). Second, scores on the anger-in subscale of the AXS were also significantly and negatively correlated with HR reactivity (df = 1,54; r = -0.31; p < .02) as well as positively correlated with pre- to posttask changes in the production of both cortisol (df = 1,52; r = 0.37; p < .007) and IL-10 (df = 1,50; r = 0.35; p < .02).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
NOTES
 ACKNOWLEDGMENTS
 REFERENCES
 
As expected, the speech task elicited a strong cardiovascular response. In addition, consistent with a number of recent studies (1–3), NKCA also increased significantly in response to the task. In contrast, task-related increases in cortisol were not observed. This is not particularly surprising considering the brief nature of the stress task. Elevated cortisol levels generally take approximately 7 minutes to be detectable in peripheral blood, and they do not peak until about 15 minutes after stimulus onset (53, 54). Researchers using similar speech tasks, such as the Trier Social Stress Task (55), have reported elevations in serum cortisol that take even longer, beginning at about 10 minutes after initiation of the stressor and peaking at about 20 minutes. Because pre- and posttask blood draws were already necessary for the assessment of NKCA and cytokine production, however, we felt that our examination of cortisol in the present study was justified.

The present study also confirmed the preliminary finding (10) that acute stress may signal an increase in at least some aspects of the cell-mediated, or TH1-driven, immune response. Specifically, in vitro production of IFN-{gamma}, a TH1 cytokine, by PBMC was significantly increased by the stressor, whereas production of IL-10, a TH2 cytokine, was not. The TH1/TH2 balance is important because each plays a distinct role in the protection of the body against pathogens. TH1 responses are most suited for protection against viruses and certain bacteria, whereas TH2 responses are better suited for protection against certain types of parasites (56). An increase in IFN-{gamma} may be a reflection not only of changes in circulating TH1 cells but also is consistent with increases in circulating CD8+ cytotoxic T cells (eg, Refs. 4, 8, 9, and 18) and NKCA, because each of these cell types is also capable of IFN-{gamma} production (57). In sum, the present results suggest that a brief speech task was sufficient to trigger an immediate cardiovascular response as well as increases in both NKCA and IFN-{gamma}, a TH1-related cytokine.

Consistent with previous findings (4, 5), changes in NKCA in response to the task also varied systematically with HR reactivity. Typically, investigators have examined HR reactivity by dividing subjects into "high" and "low" reactivity groups, thus treating reactivity as a categorical rather than a continuous variable, resulting in a loss of statistical power (eg, Refs. 6 and 8). In addition, categorizations of reactivity have often excluded a large number of "normal" subjects whose HR reactivity scores fall at or near the mean (eg, Ref. 4), limiting generalizability. In contrast, this study demonstrates a positive correlation between task-related increases in NKCA and HR reactivity without categorizing or excluding any members of the sample population, thus increasing statistical power and adding to the generalizability of the present results.1 Interestingly, a positive correlation was not found between HR reactivity and stress-related increases in the production of IFN-{gamma} by PBMC. At least two possible explanations may account for this finding. First, the mechanism of activation may differ for stress-related increases in NKCA and IFN-{gamma} production. Ackerman et al. (10) point out that although the rapidity of stress-related changes in cytokine production suggests autonomic influence, these cytokine changes also endure for relatively long periods of time, suggesting the possibility that other systemic influences might also play an important role in this process. These might include neuropeptides or other neurotransmitters (10). NKCA, on the other hand, is likely to be influenced to a large extent by the SNS (5, 9). Second, it is possible that more sensitive measures of sympathetic influence would have revealed a stronger relationship between HR reactivity and IFN-{gamma} production than the relationship that was actually observed in this study. Cacioppo and others (5, 7, 9, 20) have argued persuasively that SNS reactivity to acute stress is most sensitively measured using methods such as impedance cardiography to separate the vagal and sympathetic influences on the heart by assessing respiratory sinus arrhythmia and cardiac preejection period, respectively. If stress-related IFN-{gamma} production is in part related to SNS activation, it is possible that a stronger relationship might have been noted had the preejection period been assessed.

Although a number of neuroendocrine and immune responses to short-term laboratory stressors have now been empirically documented, these short-term responses have yet to be linked to any biologically relevant, long-term neuroendocrine or immune dysregulation. In the same manner that HR reactivity to acute stressors has been linked to such long-term problems as hypertension and heart disease (58, 59), neuroendocrine and immune system "hyper"-responsivity might lead to chronic problems with the regulation of these systems. However, because the stressful task used in the present study was brief (6 minutes), the question of whether the changes in immunity we observed in response to our stressor represent true functional differences in immunity remains unanswered. It is entirely possible, of course, that such differences are instead solely due to changes in circulating levels of PBMC, and future research is needed to examine this issue.

Another potential limitation of the present results concerns the unusually low level of lytic activity noted for both baseline and task-related NKCA. All NK cell assays were completed in duplicate, using appropriate standards, and we therefore have no reason to believe that the integrity of these assays was compromised. Nevertheless, our baseline result of 5.2% lysis is considerably lower than what would generally be expected at the 50:1 E:T ratio. Also, despite the fact that 91% of the present sample showed increased NKCA in response to the task, only 42% of the sample (22 of 53) showed task-related NKCA increases of greater than 5%, and only 23% (12 of 53) showed increases of greater than 10%. These results once again call into question the functional significance of such biological "changes" and further suggest that our NKCA results should be interpreted with caution.

Because subjects in the present study were all relatively young and healthy with no history of immune or neuroendocrine disorders, and because a longitudinal design was not feasible, we made a preliminary attempt to address this issue by examining a number of baseline parameters (NKCA; cortisol, IFN-{gamma}, and IL-10 production; and EBV antibody titers) in relation to HR reactivity. In so doing, we also made the assumption that values at baseline (ie, during a period of relative relaxation) are most likely the result of outside or real-world influence rather than a direct consequence of the experiment itself. Interestingly, this examination revealed that baseline cortisol levels were significantly predictive of HR reactivity. Animal research has shown that baseline cortisol levels are associated with a variety of socioenvironmental circumstances. For example, socially isolated male baboons exhibit basal cortisol levels that are significantly higher than those of nonisolated males (60). In addition, baseline cortisol elevations in primates have been linked to chronic exposure to an aggressive intruder (61) and to prolonged maternal separation (62). Although it is tempting to conclude that subjects highest in HR reactivity were more chronically stressed than those low in HR reactivity and that this chronic stress also contributed to higher baseline cortisol levels, we have no clear data to support this hypothesis. Instead, as is often the case with studies of reactivity, we are unable to determine whether the observed individual differences in HR reactivity were due to physiological differences between subjects, to environmental differences (ie, the high HR reactors lead more stressful lives than do low HR reactors), or to some combination of the two. Prior studies have failed to find an association between HR reactivity and baseline cortisol (eg, Refs. 4 and 6). This may be due to the relatively small samples typically used in those studies or to the loss of statistical power associated with the categorization of subjects into "high" and "low" reactivity groups. Alternatively, the present significant finding may also be attributed to the particularly stressful nature of our speech task. On average, subjects in the present study exhibited HR increases of 19.5 beats/minute and increases of 19.8 and 8.3 mm Hg for SBP and DBP, respectively. With the possible exception of DBP, these task-related increases are somewhat larger than those found in other studies of cardiovascular reactivity (eg, Refs. 4, 5, 7, 8, and 18). This leads us to speculate that large increases in HR and BP in response to the task may have helped to accentuate between-subjects differences in autonomic reactivity, making the relationship between baseline cortisol and HR reactivity easier to detect. In any case, the present finding that baseline cortisol levels were significantly related to HR reactivity is both provocative and in need of further exploration.

Our inability to find a significant relationship between HR reactivity and antibody titers to EBV is interesting, particularly given that a number of researchers have successfully linked EBV antibody expression to stressors of longer duration (63–66). Although it is possible that the magnitude of sympathetic reactivity to acute stressors is simply unrelated to the expression of EBV, it is also possible that the present study failed to identify a significant relationship because of the youth and relative health of the subjects examined. Cacioppo et al. (20) note that if reactivity to stress influences health through cellular senescence, we may infer that any health consequences related to stress reactivity would be more easily detectable in an aged or otherwise immunocompromised population. Therefore, it remains conceivable that a replication of the present study with elderly subjects, a population for whom the ability to mount an antibody response to a previously encountered antigen like EBV is diminished (67), would reveal the hypothesized relationship. Alternatively, Glaser et al. (68) report within-subject increases in EBV antibody titers during final examinations for West Point cadets but not during a 6-week period of basic training. Thus, reactivation of latent EBV may also be stressor-dependent.

Finally, two mildly interesting findings were derived from our attempts to relate scores on the psychological measures to HR, immune, and neuroendocrine function. First, based on previous research (33), we had anticipated that high TMAS scores would be positively related to EBV antibody titers. This was not the case. Instead, TMAS scores were found to be negatively correlated with HR reactivity. Although a negative correlation is somewhat counterintuitive in this instance, this finding might be explained by previous studies of so-called "repressive copers." Specifically, researchers have reported increased cardiovascular reactivity (69) to stress in individuals who exhibit the repressive coping style, defined as those scoring below the median on the TMAS and above the median on the MCSDS, as compared with nonrepressive copers. However, post hoc analysis failed to replicate this result in the present sample, leaving the observed negative correlation between the TMAS and HR reactivity unexplained. It is worth pointing out that at least one recent study (70) also reports a negative relationship between trait anxiety and cardiovascular reactivity, although this relationship was reported to be quite weak and of questionable biological significance. The second interesting finding from the psychometric data were that the anger-in subscale of the AXS was found to negatively correlate with HR reactivity and to positively correlate with pre- to posttask changes in the production of cortisol and IL-10. This is particularly interesting when one considers that neither cortisol nor IL-10 production was found to significantly increase in response to the task. High anger-in scores have been linked to a variety of health-related problems, including an increased risk of hypertension (71), carotid atherosclerosis (72), and chronic pain (73), and the present results are certainly worthy of further exploration. As a final word of caution, however, it should also be noted that a large number of regression equations were computed in the analysis of the aforementioned psychological data (almost 40), and therefore, using the p < .05 level of significance, we must conclude that the so-called "significant" findings above may have simply been due to chance.

In summary, HR, blood pressure, NKCA, and IFN-{gamma} all increased in response to an acute laboratory stressor. Task-related increases in NKCA were significantly related to HR reactivity, whereas task-related increases in IFN-{gamma} and baseline antibody titers to EBV were not. In addition, baseline cortisol levels were found to be predictive of HR reactivity. Finally, various aspects of HR, immune, and neuroendocrine reactivity to the task seem to be at least modestly related to the decreased experience of anxiety and to increased anger suppression. Based on the task-related increases in NKCA and IFN-{gamma} production, we may conclude that the acute stress response is consistent with an increase in at least some aspects of the cell-mediated, or TH1-driven, immune response. Furthermore, the finding that baseline individual differences in cortisol production are related to HR reactivity suggests that short-term cardiovascular responses to stress may be directly related to longer-term neuroendocrine modulation. Finally, the present results highlight the influence of both sympathetic and nonsympathetic pathways in the response to acute stressors and suggest a relationship between autonomic reactivity and some aspects of cytokine function. Future research is needed to examine the extent to which these acute immune responses may prove to be of biological significance.


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
 ACKNOWLEDGMENTS
REFERENCES
 
This research was supported by an Institutional Training Grant (MH18822) from the National Institute of Mental Health; by the Center for Psychoneuroimmunology Research through a grant from the Fetzer Institute; and by a General Clinical Research Center Grant (5 MO1 RR00044) from the National Center for Research Resources, National Institutes of Health.


   NOTES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
ACKNOWLEDGMENTS
 REFERENCES
 
For the record, post hoc analysis using a similar regression strategy but only the highest and lowest quartiles based on HR reactivity (ie, eliminating the middle two quartiles) resulted in a stronger correlation (N = 26, r = 0.573, p < .003) despite the 50% reduction in sample size. Back

Received for publication December 7, 1999.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
 ACKNOWLEDGMENTS
 REFERENCES
 

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