This study examined the effects of acute stress on changes in monocyte cell surface expression of β2
-integrins in healthy, non-smoking adults. In examining these associations, we specifically examined changes in the arousal of NA, cardiovascular reactivity and adrenergic reactivity to the ARI, an ecologically valid laboratory stressor (Suarez et al., 2004b
). The principal findings were that the ARI, on average, induced a decrease in monocyte expression of β2
-integrins. However, individuals who showed the largest increases in NA, Ne and DBP during the ARI showed an increase in monocyte β2
-integrin expression, consistent with greater cellular adhesion to the vascular endothelium (Gamberg et al., 1998
). These results were observed in a large sample of apparently healthy men and women with each quartile having approximately 40–44 subjects. The reported observations were statistically independent of age, sex, BMI, exercise status and baseline β2
-integrin expression. Other potential confounding factors were methodologically controlled. These included smoking history, historical or current clinical disease, medication use, and for women, menstrual cycle phase and oral contraceptive use.
Results further revealed that the ARI task induced an increase in circulating monocyte numbers. This observation is consistent with previously reported data by other investigators who have used either an evaluative speech paradigm (Mills et al., 2003
) or an exercise task (Hong and Mills, 2008
). The observed stress-induced monocytosis is also consistent with the widely reported leukocytosis following participation in acute psychological stressors (Benschop et al., 1996
). We also observed a mean decrease in CD11a expression on circulating monocytes following the ARI. This task-related decrease is consistent with observation by Mills et al. (2003)
who showed a similar task-related decrease in CD11a cell surface density on monocytes following the evaluative speech stressor (Mills et al., 2003
). The current study extends previous observations by Mills and colleagues by suggesting that, on average, the ARI evoked significant decreases in monocyte expression of two other β2
-integrins, CD11b and CD11c.
It is important to note that the observation of task-related decreases in surface marker expression does not take into account individual differences in emotional and physiological responses to the task. The assessment of individual differences in stressor appraisal, such as intensity of emotional arousal, is particularly important given the well-established observation that laboratory stressors do not evoke homogeneous physiological responses. In our study, task level analysis suggested that participation in the ARI led to overall mean decreases in integrin expression on circulating monocytes. These results are consistent with results of regression analyses, which indicated that most individuals showed a decrease in monocytic β2
-integrin expression. However, employing only a task-related analytic approach failed to identify an important subgroup of individuals (e.g., the top quartile of reactors) that expressed an increase in cell surface markers thought to promote atherosclerotic disease. Surprisingly, most studies that have examined stress-induced changes in cell surface markers have not included individual difference level analysis to accompany task level analysis (e.g., Goebel and Mills, 2000
; Mills et al., 2003
). The differences in the results of these analytic approaches underscore the need for future studies to incorporate individual difference analyses in order to better understand the role of emotional and physiological reactivity to stress and how these responses may contribute to disease susceptibility (Lovallo and Gerin, 2003
The findings of the current study extend previous observations in other novel ways. In addition to characterizing immunological/ inflammatory responses to the ARI, a task that has not been frequently used in psychoneuroimmunology studies (e.g., Suarez et al., 2006
), the current study is the first to provide empirical evidence of the importance of individual differences in arousal of NA and sympathetically driven physiological responses (i.e., cardiovascular and adrenergic activation) on changes in monocyte expression of β2
-integrins. Given the role of monocytes in the pathogenesis of atherosclerotic cardiovascular disease, the pattern of observations suggests that stress-induced changes in monocyte cell surface markers represent a pathway whereby negative affect could contribute to increased risk of future cardiovascular disease development.
The current findings may also shed light on the equivocal nature of previous observations describing monocyte surface marker responses to acute laboratory stressors. As noted, studies have reported either decreases (Mills et al., 2003
) or no change (Goebel and Mills, 2000
) in monocyte cell surface expression of CD11a in response to the evaluative speech stressor. One possible explanation for this inconsistency is that individuals differed in arousal of NA and/or sympathetically-driven physiological responses between the two studies. Another possibility is that small sample size contributed to the mixed results. Based on our findings, it is conceivable that laboratory stressors that evoke significant arousal of NA in only a few subjects produce an overall decrease in surface markers, or perhaps no change at all on average. This possibility is particularly salient to studies that have small samples sizes (e.g., <50) of healthy individuals where it is possible that the number of subjects who exhibit increases in cell surface marker expression is small.
There are a number of plausible explanations for the current findings. One possibility is the influence of cytokines and chemokines in activating peripheral monocytes and upregulating β2
-integrin expression (Johnston and Butcher, 2002
). In previous studies, we showed that psychological distress and arousal of NA are associated with both increased expression and production of proinflammatory cytokines and chemokines by peripheral monocytes (Suarez et al., 2003
; Suarez et al., 2006
). Others have shown that proinflammatory cytokines and chemokines can directly stimulate leukocyte activation and firm adhesion to endothelial cells by rapidly mobilizing integrin molecules to the cell surface (Fabbri et al., 1999
). Taken together, the data suggest that arousal of NA may initiate a cascade of events that leads to increased cell surface marker expression via production of proinflammatory cytokines and chemokines that, alone or in combination, activate peripheral monocytes.
Another possible explanation is that stress-related changes in leukocyte expression of β2
-integrins is modulated by catecholamines in conjunction with the level of β-adrenergic receptor expression and the specific leukocyte subset examined (Carlson, 1997
; Mills et al., 1998
-adrenergic receptor stimulation by catecholamines has been shown to upregulate integrin expression via activation of an intracellular signaling pathway that involves a G-protein signal-transduction mechanism (Padgett and Glaser, 2003
). In our laboratory, we have demonstrated β2
-adrenergic receptor functional dysregulation in response to pharmacologic stimulation among high hostile men (Suarez et al., 1998
). Combined, these observations suggest that stress-induced sympathetic outflow in the presence of altered β2
-adrenergic receptor functioning could lead to increases in cellular adhesion.
Finally, it is also possible that changes in β2
-integrin expression on monocytes are due to a sympathetically mediated increase in circulatory shear stress, which is associated with endothelial cell activation, vascular proinflammatory cytokine and chemokine production, preferential expression of integrins on circulating leukocytes, and extravasation into the vascular wall (Fabbri et al., 1999
; Krieglstein and Granger, 2001
). Therefore, to the extent that arousal of NA stimulates proinflammatory processes and sympathetic activation, it is conceivable that a number of different, interactive cellular and molecular mechanisms could, in part, explain the relationship between the acute arousal of emotional distress and changes in CAM expression on circulating monocytes.
The participants in the present study were nonsmokers and were free of medications, including those known to influence immune regulation and inflammation. In addition, regression models statistically controlled for the potentially confounding influences of age, sex, BMI, exercise regularity, and baseline level of monocytic β2
-integrin expression. It is possible, however, that unmeasured variables may account, in part, for the observed findings. For instance, it has recently been shown that variations in anticipatory cognitive stress appraisal accounts for monocyte production of proinflammatory cytokines in men following a psychosocial laboratory stressor (Wirtz et al., 2007
). Additionally, participants’ tendency to ruminate about anger-provoking events may have, in part, accounted for the magnitude of association between the arousal of NA and changes in monocyte β2
-integrin expression following the ARI.
In conclusion, the present investigation provides experimental evidence for a plausible psychoimmunological mechanism underlying the established relationship between higher levels of NA and greater susceptibility to ACVD. Specifically, data revealed that heightened stress-induced arousal of NA during a brief anger recall task was associated with increased expression of β2-integrins on peripheral blood monocytes, a phenotypic change that is instrumental for the adhesion of monocytes to the endothelium in the early stages of atherosclerosis. These findings further demonstrated that stress-induced sympathetic activation selectively predicted increased monocytic cell surface expression of CAMs associated with vascular inflammation. Future research is warranted to (a) investigate the association between arousal of NA and other CAMs implicated in atherosclerosis, and (b) test the possibility that emotion regulation skills modulate individual differences in stress-related changes in CAM expression.