Mounting evidence suggests that chronic interpersonal stressors have a detrimental influence on mental and physical health, and one emerging hypothesis regarding the mechanism of these effects involves the ability of stress to alter physiologic inflammatory processes. The present results support that hypothesis in identifying significantly greater 6-month increases in expression of gene products involved in the transduction of inflammatory signals (NF-κB, GR-β, and IκB mRNA) in leukocytes from young people who experienced chronic interpersonal stress. These alterations in inflammatory gene expression appear to have significant consequences for leukocyte functional responses to stimulation. In response to a model bacterial stimulus (LPS), leukocytes from those showing higher levels of interpersonal difficulty showed greater increases over time in the production of the pro-inflammatory cytokine IL-6 than did cells from those experiencing low levels of interpersonal difficulty. These conflict-related changes in expression of inflammatory signaling pathway genes appear to predominately affect the leukocyte’s potential to respond to a pathogen challenge, rather than its basal production of pro-inflammatory cytokines. That is, subjects experiencing high levels of interpersonal difficulty at baseline did not show elevations in serum biomarkers of basal inflammatory activity (i.e., circulating IL-6 or CRP). Differences only emerged when inflammatory signal transduction pathways were actively engaged by a model stimulus (i.e., in LPS-stimulated production of IL-6 ex vivo).
These results imply that, at least in young healthy people with comparatively low levels of chronic inflammation, social conflict creates a potential for hyper-inflammatory responses that requires an exogenous immunological stimulus for realization. Thus, any health consequences of these dynamics, would likely involve a person x situation interaction in which interpersonal difficulties (person) acts to amplify the effects of a pathogenic insult (situation) to impact inflammation-related disease pathogenesis. Such dynamics could have relevance in a number of mental and physical illnesses that are known to be exacerbated by interpersonal difficulties. For example, depression is particularly sensitive to inflammation, and so are a number of infectious, metabolic, and coronary diseases 15–17,29
The mechanisms responsible for stress-related changes in inflammatory signaling remain to be elucidated. Because of the project’s strict inclusion criteria and use of statistical controls, we can be reasonably confident that lifestyle variables, psychiatric conditions, medical illnesses, and demographic factors are not responsible for the observed relationship between interpersonal difficulties and altered inflammatory signaling. One plausible hypothesis is that sympathetic nervous system activation underlies this phenomenon. Acute bouts of social conflict provoke the release of norepinephrine 30
, which can potentially increase NF-κB expression or enhance its DNA binding activity 31
. However, the available evidence suggests that these dynamics unfold over fairly short periods of time and, as such, they would be expected to manifest in a “real-time” association between interpersonal difficulties and inflammatory parameters. By contrast, our data suggest that there is a time lag, of up to six months, between exposure to social stress and changes in leukocyte functions.
To some degree cortisol may help to explain these time-lagged patterns. Individuals without a regular schedule of warm social contacts tend to have unstable rhythms of HPA output 32,33
. With repeated exposure to high doses of cortisol over time, such persons may eventually become resistant to the hormone’s influence. In the immune system the development of such resistance would enable inflammation to flourish without its usual hormonal constraints 23,34
. In fact, chronic social stress has been shown to foster resistance to the anti-inflammatory properties of glucocorticoids in rodent models 13,35
. And similar dynamics have been found in humans: recent genome-wide microarray experiments demonstrate that people who are chronically lonely or facing significant interpersonal stress., e.g. caring for a spouse with cancer, show heightened NF-κB activity and simultaneous impairment of cortisol-mediated signaling 34,36
. Collectively, these results suggest that social difficulties may provoke HPA abnormalities, which over time foster resistance to glucocorticoids and expression of inflammatory mediators. The time required for this chain-of-events to unfold may help to explain why our data yielded evidence of prospective associations between interpersonal difficulties and inflammatory processes, but no cross-sectional relationships.
This study had several limitations worth noting. First, because the sample was chosen to be at high-risk for depression, they are not representative of the general population. Though this constrains the generalizability of the findings, it does not seriously complicate interpretation of them. Future research will need to be done, however, to substantiate the effects in the broader population. Second, the study quantified mRNA for inflammatory signaling molecules, but did not measure their associated proteins or directly assess the functional activity of each individual protein (although the integrated activity of the pathway as a whole was assayed using the LPS stimulation model). Assessment of individual protein alterations will need to be done in future research. Third, the study only had two points of inflammatory assessment. As a result, we are unable to specify how long the “incubation period” is between exposure to interpersonal difficulties and subsequent alterations in inflammatory processes. Without more points of assessment, we are also unable to specify if and when these alterations resolve, or what influence earlier social conflict had on biological processes captured at study entry. Multiwave studies will be needed to address these questions. Fourth, the sample was composed of young women who, on average, had fairly good social relations and limited amounts of systemic inflammation. The modest stress levels may have somewhat restricted the magnitude of associations we were able to observe, and the low CRP and IL-6 values may explain why these outcomes were unrelated to interpersonal difficulties in our sample, but have been linked to stress in other projects, e.g.
. Finally, we did not measure any clinical outcomes in this project, so it remains unclear whether these dynamics have disease implications. It will be important for the next wave of studies in this area to do so, and determine whether inflammatory processes are the mechanism through which chronic interpersonal stress “gets under the skin” to undermine mental and physical health. In the meantime, these findings extend into humans a large corpus of animal research 37,38
suggesting that an organism’s physiology is intimately regulated by the social context in which s/he resides.