Synergistic effects of psychological and immune stressors on inflammatory cytokine and sickness responses in humans

Abstract

Activation of the innate immune system is commonly accompanied by a set of behavioural, psychological and physiological changes known as 'sickness behaviour'. In animals, infection-related sickness symptoms are significantly increased by exposure to psychosocial stress, suggesting that psychological and immune stressors may operate through similar pathways to induce sickness. We used a double-blind, randomised, placebo-controlled design to examine the effect of acute psychological stress on immune and subjective mood responses to typhoid vaccination in 59 men. Volunteers were assigned to one of four experimental conditions in which they were either injected with typhoid vaccine or saline placebo, and then either rested or completed two challenging behavioural tasks. Typhoid vaccine induced a significant rise in participants' serum levels of interleukin-6 (IL-6) and this response was significantly larger in the stress versus rest conditions. Negative mood increased immediately post-tasks, an effect also more pronounced in the vaccine/stress condition. In the vaccine/stress group, participants with larger IL-6 responses had heightened systolic blood pressure responses to tasks and elevated post-stress salivary levels of the noradrenaline metabolite 3-methoxy-phenyl glycol (MHPG) and cortisol. Our findings suggest that, as seen in animals, psychological and immune stressors may act synergistically to promote inflammation and sickness behaviour in humans.

Figures

Fig. 1

Subjective stress ratings at baseline (Base), during each of the tasks (Stroop, Speech) and at 30, 60 and 120 min post-tasks. Comparison of stress (solid lines) and rest (dotted lines) conditions in participants receiving typhoid vaccine (circles) or saline placebo (squares). Data are presented as means ± SEM.

Fig. 2

Systolic blood pressure (A), diastolic blood pressure (B), and heart rate (C) at baseline (Base), during each of the tasks (Stroop, Speech) and at 25–30, 55–60 and 115–120 min post-tasks. Comparison of stress (solid lines) and rest (dotted lines) conditions in participants receiving typhoid vaccine (circles) or saline placebo (squares). Data are presented as means ± SEM.

Fig. 3

Salivary 3-methoxy-phenylglycol (MHPG) concentrations before (Base), immediately following tasks (post-task) and at 15, 30, 60 and 120 min post-tasks. Comparison of MHPG stress responses in participants receiving typhoid vaccine (circles) or saline placebo (squares). MHPG was assessed using gas chromatography mass spectrometry. Distributions of MHPG were skewed, so were log transformed prior to analyses. Data are presented as log means ± SEM.

Fig. 4

Serum interleukin-6 (IL-6) concentrations before (Base) and 120 min post-tasks (120 min post-task). Comparison of stress (solid lines) and rest (dotted lines) conditions in participants receiving typhoid vaccine (circles) or saline placebo (squares). IL-6 was measured using a high-sensitivity two-site ELISA. Distributions of IL-6 were skewed, so were log transformed prior to analyses. Data are presented as log means ± SEM.

Fig. 5

Total negative mood scores at baseline (Base), immediately following tasks (post-task) and at 30, 60 and 120 min post-tasks. Comparison of stress (solid lines) and rest (dotted lines) conditions in participants receiving typhoid vaccine (circles) or saline placebo (squares). Data are presented as means ± SEM.

Fig. 6

Scatter plot illustrating the relationship between systolic blood pressure responses to the Speech task and changes in serum interleukin-6 (IL-6) levels, in the vaccine/stress group.