This study examined the relationship between chronic stress, acute events and within-person changes in cytokine production over two years in children with asthma and a healthy comparison group. Within the asthma group, we found that the association between acute events and asthma-relevant cytokines was accentuated among children with chronic family stress. Specifically, children with high chronic family stress showed increased production of IL-4, IL-5, and IFN-γ at times when they had experienced an acute event compared to times when they had not. In contrast, when chronic family stress was low, there was no relationship between acute events and cytokine production. Acute and chronic stress did not interact to predict cytokine changes among medically healthy children, suggesting that the cytokine changes are specific to asthma and not simply part of a general response to stress. Furthermore, in a subgroup of children with moderate to severe asthma, acute and chronic stress interacted to predict asthma symptoms, such that children who were exposed to both acute and chronic stress reported the most severe symptoms. This pattern of results mirrors previous clinical findings in which double-exposure to acute and chronic stressors was associated with risk for asthma exacerbations (2
). The present study takes this research one step further by providing a plausible biological explanation for how a psychological factor like stress can influence clinical outcomes in asthma.
One reason why double-exposure may be so detrimental is that it may be that while people can manage one key life stressor, they do not have the resources (e.g., time, energy, social support) to deal with multiple stressors effectively. This might prolong the impact or heighten the severity of stressors that could normally be managed. Having to juggle multiple stressors also seems likely to interfere with people's ability to engage in healthy behaviors like exercising and spending time with friends, that can protect against the detrimental influence of problems at home, work, and school. Double-exposure may also overwhelm a person's social-support network or, if one of the stressors involves tensions with close friends or family, interfere with his or her ability to mobilize it. Erosion of family support could be especially detrimental for children, who often rely on their parents and siblings for assistance with key life events.
What are the mechanisms by which double-exposure influences cytokine production? One possibility is that stress-related activation of the hypothalamic-pituitary-adrenocortical axis and the sympathetic nervous system among double-exposed children leads over time to a compensatory down-regulation of glucocorticoid and β-adrenergic receptors on target tissues. This process is thought to decrease sensitivity to the anti-inflammatory effects of hormones like cortisol and epinephrine (18
). Consistent with this theory, double-exposure has been linked to elevated cortisol output through the day and decreased expression of glucocorticoid receptor mRNA among healthy young women (24
), as well as decreased expression of both glucocorticoid and β-adrenergic receptor mRNA among youth with asthma (18
). Thus, the present findings of heightened cytokine production may in part result from diminished control over inflammation due to dysregulation at the level of hormones and receptors. Future work would benefit from prospective studies that examine the causal relations between stress exposures, hormone dynamics, and asthma-related immune markers.
This study examined T-helper (TH
) 2 (IL-4, IL-5, and IL-13) and TH
1 (IFNγ) cytokines, which serve different functions during an immune response. In regard to asthma, it is widely believed that the inflammatory response involves a TH
2 mechanism (25
). In addition, there is some evidence that acute stress involves a shift toward a TH
2 response (increased production of IL-10) and away from a TH
1 response (decreased production of IFN-γ) among healthy young adults (28
). Consistent with these findings, double-exposed children with asthma in our sample showed increased TH
2 cytokine (IL-4 and IL-5) production which could be indicative of an enhanced humoral response to allergens. However, they also showed increased production of IFN-γ, a TH
1 cytokine that is thought to have inhibitory effects on TH
2 pathways. These results are consistent with some previous research- for example, the finding that another type of chronic stress, low socioeconomic status, is associated with elevations in both TH
2 (IL-5) and TH
1 (IFN-γ) responses among children with asthma (29
). Thus, it may be that in children with asthma, stress leads to a general upregulation of TH
cell activity and signaling (rather than an imbalance between TH
1 and TH
2). What this means for asthma is unclear. Though Th1 activity generally inhibits the Th2 signals that drive asthma, some data suggest that cytokines like IFNg contribute to asthma pathogenesis, possibly by orchestrating anti-viral immune responses in the lungs (30
). If this is the case, stress-related priming of IFN-g responses could have detrimental influences on asthma symptoms, especially when they have been triggered by viral infection (1
This study showed that, among children with moderate to severe asthma, acute stress and chronic family stress interacted to predict asthma symptoms. The pattern of the interaction was similar to the interaction of acute and chronic stress predicting IL-4, IL-5, and IFN-γ production. However, in addition to the pattern found with cytokines, chronic family stress also appears to influence asthma symptoms in the absence of an acute event. Specifically, when no event had occurred, chronic family stress was positively associated with asthma symptoms, but to a lesser degree than after an acute event. The difference in patterns for cytokine production versus symptoms suggests that there are pathways in addition to immune changes by which chronic family stress can influence symptoms (32
But, are the observed increases in IL-4, IL-5 and IFN-γ production really relevant to asthma? To test this question, we also examined the relationship between cytokine production and asthma symptoms among subjects with higher severity asthma. Results indicated that increased production of IL-5 was associated with within-person increases in asthma symptoms, and there was a trend toward a similar effect for IL-4 production. This provides evidence that changes in IL-5 and IL-4, but not IFN-γ, production are relevant to asthma symptoms.
This study has a number of limitations. First, it is possible that unmeasured variables account for our effects. For instance, increased risk for infection following life events could explain the relations of acute events to cytokine production. However, if this were the case, one would expect to see effects of infection on both the main effect of stressful events as well as the interaction between acute and chronic stressors. Moreover, the within-person nature of our analyses and findings precludes most of the alternative explanations for linkages between stressors and immunity (e.g., genetics, lifestyle factors). Second, it will be important to see how factors like gender and puberty moderate the effects of double-exposure on cytokine production; however, in the present study, we did not have enough power to test these 3-way interactions. Third, our inability to detect main effects of acute events may reflect the fact that cytokine production was not always assessed shortly after the stressor occurred, when they would be most likely to emerge. Future research that examines inflammatory processes within weeks of the stressful event may be more likely to detect such findings. Fourth, immune processes were measured from peripheral blood cells. Future studies that are able to obtain cells directly from the airways would provide important information about more proximal processes. Fifth, the cytokine production assay used a substance that stimulates cells nonspecifically, rather than through the antigen-specific pathways that are engaged by most allergens in the body. However, given that our sample was not selected for a positive response to any specific allergen, the use of a specific stimulus would not have elicited responses across all children. Finally, it should be noted that youth were recruited into this study on the basis of parent reported physician diagnosis of asthma and that physician diagnosis is not always accurate. However, if we inadvertently included some children who did not truly have asthma, this in theory would add noise to our measurements, making it more difficult to detect associations.
Despite these limitations, our findings provide several important contributions to the literature. First, they suggest that stressor impact is a complex phenomenon- the combination of acute and chronic stress may be necessary to produce a change in cytokine production. Second, the immune changes observed among children who had been exposed to acute and chronic stress are relevant to asthma symptomatology. Third, this type of research contributes to biopsychosocial models that seek to explain how larger social factors can get “under the skin” to affect an individual child's health. The fact that experiencing an acute life event on top of high chronic stress predicts detrimental inflammatory responses suggests that psychosocial interventions aimed at helping children manage stress could have implications biologically for children with asthma.