Chronic interpersonal stress predicts activation of pro- and anti-inflammatory signaling pathways 6 months later

Abstract

Objective: To understand the mechanisms underlying chronic interpersonal difficulties and their detrimental influence on mental and physical health.

Methods: A total of 103 healthy young women (mean age = 17 years) were administered a structured interview to assess the degree of chronic interpersonal stress in their lives. At the same time, blood was drawn to measure systemic inflammation, the expression of signaling molecules that regulate immune activation, and leukocyte production of the cytokine interleukin-6 after ex vivo stimulation with lipopolysaccharide. All of the immunologic assessments were repeated 6 months later.

Results: To the extent subjects were high in chronic interpersonal stress at baseline, their leukocytes displayed greater increases in messenger ribonucleic acid (mRNA) for the proinflammatory transcription factor nuclear factor-kappaB (NF-kappaB) over the next 6 months. They also showed larger increases in mRNA for inhibitor of kappaB, a molecule that sequesters NF-kappaB in the cytoplasm and minimizes its proinflammatory activities. Chronic interpersonal stress at baseline was unrelated to changes in biomarkers of systemic inflammation but was associated with increasingly pronounced interleukin-6 responses to lipopolysaccharide. These associations were independent of demographics, lifestyle variables, and depressive symptoms.

Conclusions: These findings suggest that chronic interpersonal difficulties accentuate expression of pro- and anti-inflammatory signaling molecules. Although this process does not result in systemic inflammation under quiescent conditions, it does accentuate leukocytes' inflammatory response to microbial challenge. These dynamics may underlie the excess morbidity associated with social stress, particularly in inflammation-sensitive diseases like depression and atherosclerosis.

Figure 1

LPS-stimulated production of interleukin-6 increases over time in subjects with chronic interpersonal stress. For the purpose of illustration, the sample was stratified at the median of chronic interpersonal stress (2.4 on a 1–5 scale), and the groups’ IL-6 values were compared using a repeated-measures ANOVA. Covariates included age, ethnicity, oral contraceptives, socioeconomic status, central adiposity, and physical activity. The analysis yielded a significant Stress X Time interaction, F (1,95) = 4.11, p = .05, indicating that the low and high stress groups changed differentially over the 6-month follow-up. Data are plotted as mean + standard error.