Acute inflammation and negative mood: Mediation by cytokine activation

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Abstract

Inflammatory diseases are commonly associated with depressed mood. This association may be influenced by the production of proinflammatory cytokines. Accordingly, we assessed whether cytokine levels and mood (measured with the profile of mood states) could be altered by a mild, non-sickness inducing, acute inflammatory stimulus. Using a randomised placebo-controlled, double-blind design, 30 healthy male volunteers were injected with Salmonella typhi vaccine or placebo. Assessments of mood, symptoms of illness and temperature were made at baseline and at 1.5, 3, and 6 h post-injection. Plasma concentrations of interleukin-6 (IL-6), interleukin-1 receptor antagonist (IL-1Ra), and tumour necrosis factor-α (TNF-α) were assessed at baseline and 3 h post-injection. No significant symptoms of illness were reported in either group. Mood was more negative following injection in the vaccine than the placebo group, and the vaccine group experienced a 106% increase in IL-6 concentration. Negative changes in mood following injection were significantly correlated with increases in IL-6 production. No changes in TNF-α or IL-1Ra concentration were recorded in either group. It is concluded that S. typhi vaccination may be a useful model of mild inflammatory challenge, producing a significant transient cytokine-induced decrease in mood in the absence of any febrile response. Implications for depressed mood in physical illness are discussed.

Introduction

Infectious and inflammatory diseases are associated with numerous behavioural disturbances including malaise, lethargy, anorexia, hyposomnia, inactivity, impaired cognition, and anhedonia (Larson and Dunn, 2001). Once merely regarded as an unpleasant side-effect of illness, it is now believed these behaviours form part of a natural homeostatic reaction used to fight infection (Hart, 1988). This process, termed ‘sickness behaviour,’ is triggered by proinflammatory cytokines including interleukin-1 (IL-1), interleukin-6 (IL-6), and tumour necrosis factor-alpha (TNF-α) (Konsman et al., 2002).

Elevated cytokine levels are also associated with major depression (Irwin, 2002) , although evidence relating cytokines to sub-clinical depressive symptoms is inconsistent (Haack et al., 1999, Kop et al., 2002, Miller et al., 2003, Steptoe et al., 2003). Cancer patients with depression have higher plasma concentrations of IL-6 than healthy controls or cancer patients without depression (Musselman et al., 2001a), and depressive symptoms are common in conditions associated with cytokine activation, including autoimmune diseases, stroke, trauma and Alzheimer’s disease (Yirmiya, 1997, Yirmiya et al., 1999). However, a critical issue is the causal direction of these associations. It has been argued that depressed mood stimulates inflammatory responses, and that this mechanism might contribute to the adverse consequences of depression in conditions such as acute coronary heart disease (Black and Garbutt, 2002). There is also evidence that anti-depressant treatments which target the neurochemical basis of depression have anti-inflammatory effects (Castanon et al., 2002, Musselman et al., 2001b). In addition, however, it is believed that inflammatory responses may actively contribute to depressive mood and negative affect. Studies of patients with cancer indicate that immune therapy using IL-2 or interferon-α leads to depressed mood that correlates with the magnitude of endogenous cytokine responses (Capuron et al., 2001), and depressive symptoms have also been reported following interferon-α treatment of hepatitis C (Bonaccorso et al., 2001).

Results from clinical samples may not generalise to the population at large since they involve participants with already compromised immune systems. A more controlled and predictable inducer of inflammatory response is therefore required in order to understand the relationship between inflammation and depression. As a result, research has begun to manipulate acute transient inflammatory responses through vaccination and injection of active endotoxins in humans.

The acute effect of an infectious stimulus upon mood in healthy volunteers was investigated by Reichenberg et al. (2001). Using Salmonella abortus equi endotoxin as a model of experimental inflammation, this double-blind placebo-controlled study observed a 50- to 100-fold increase in IL-6 and TNF-α concentrations within 1–4 h of endotoxin, but not placebo administration. Significant increases in anxiety and depressed mood were reported in the endotoxin but not placebo group. Although endotoxin had no effect on blood pressure, heart rate or reported sickness, it did cause an increase in body temperature and a marked reduction in food intake. This made it difficult to determine whether behavioural and mood changes were due to inflammatory challenge, or were caused by the mild illness induced by the endotoxin itself. In light of these findings, our group investigated a milder model of experimental inflammation, namely typhoid (Salmonella typhi) vaccination (Strike et al., 2004). Results indicated that typhoid vaccination led to a significant decline in mood over an 8 h period in comparison with placebo, without inducing any physical symptoms or temperature increase. Typhoid vaccination has previously been shown to produce a 4–6-fold increase in IL-6 and a 30-fold increase in IL-1Ra within 2–3 h (Hingorani et al., 2000, Kharbanda et al., 2002). The use of vaccination rather than endotoxin may afford better insight into changes of mood state in response to immune challenge in healthy volunteers. However, our previous study did not include measures of cytokines, so we were not able to directly test the influence of inflammatory responses on mood changes. The present study was therefore designed firstly to replicate previous findings on the effects of typhoid vaccination on subsequent mood, and secondly to assess the mediating role of cytokine responses. We hypothesised that typhoid vaccination (in comparison with placebo) would induce significant increases in IL-6, IL-1Ra, and TNF-α, teamed with a decline in mood, in the absence of any change in systemic body temperature or symptom ratings of illness.

Section snippets

Participants

Thirty male student volunteers aged between 18 and 30 years (mean 23.3 ± 3.5) were recruited from University College London. Participants were all non-smokers, were not on regular medication, and had no recent mental or physical illness or a typhoid vaccination within the last 6 months. On the morning of the study all participants felt well, had no recent stressful events and had refrained from caffeine, alcohol and physical exercise for 12 h before the start of the study. Ethical approval was

Results

Sample characteristics and baseline measures are summarised in Table 1. The vaccine and placebo groups did not differ significantly in age or physiological measures. Mood scores indicate that participants demonstrated a slight overall negative mood at baseline. Mood scores did not differ significantly between groups. None of the participants reported any appreciable symptoms pre-injection.

Discussion

Inflammatory diseases are typically associated with depressed mood. This study hypothesised that a mild experimentally induced inflammatory response would produce a transient decline in mood, and that this association would be mediated by cytokine activation. Due to the possible confounding effects of experimenter and participant expectations, the hypothesis was tested using a double-blind design. The placebo-controlled design was also used in order to account for spontaneous circadian mood

Acknowledgments

The study was supported by the British Heart Foundation and Medical Research Council. We are grateful to Bev Murray and Lindsey Emerson for their assistance with vaccination.

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