Cortisol responses to mild psychological stress are inversely associated with proinflammatory cytokines
Introduction
The physiological stress response consists of an activation of the sympathetic nervous system (SNS), a parasympathetic withdrawal, and increased activity of the hypothalamic–pituitary–adrenal (HPA) axis, with wide individual differences and consequences. As these systems interact with the immune systems via different pathways (Felten and Felten, 1994), stress also influences immune functions (Abraham, 1991; Maier and Watkins, 1998). Impaired immune competence has been shown in individuals experiencing chronic stress and may lead to increased risk of infectious disease (Herbert and Cohen, 1993; Cohen et al., 2002). In contrast to chronic stress, acute stress not only activates the SNS and HPA axis, but also parts of the immune system (Abraham, 1991; Maier and Watkins, 1998). Recent findings suggest that proinflammatory cytokine production increases in response to acute psychological stress in humans (Maes et al., 1998; Steptoe et al., 2001). The first part of the acute stress response characterized by an activation of the SNS is accompanied by an increase in immune cell numbers, such as B-cells (Landmann et al., 1984) and natural killer cells and their activity (Benschop et al., 1996), but is also marked by an increase in IL-1ra and IL-6 that may take several minutes to evolve (Shephard, 2002). Glucocorticoids modulate cytokine production and receptor expression (Wiegers and Reul, 1998). It is thought that glucocorticoids play a beneficial role during acute stress, but that during chronic stress the effects of glucocorticoids on immune functions are detrimental (Van den Berghe et al., 1998).
There is an important feedback loop between cytokines and glucocorticoids: proinflammatory cytokines, such as interleukin-1 (IL-1) and interleukin-6 (IL-6) are potent activators of the HPA axis (Turnbull and Rivier, 1999). Glucocorticoids in turn negatively control cytokine production and by this mechanism are able to shut down inflammatory processes to prevent host destruction due to prolonged immune activity (Besedovsky and del Rey, 2000; Sapolsky et al., 2000). IL-6 is secreted from a number of different cells, such as activated macrophages, lymphocytes, adipocytes, and skeletal muscle (Febbraio and Pedersen, 2002; Mohamed-Ali et al., 2001). It is negatively controlled by glucocorticoids and positively controlled by catecholamines (Baker et al., 2001), and in turn regulates immune responses, acute phase protein synthesis, and hematopoiesis (Turnbull and Rivier, 1999). Interleukin-1 receptor antagonist (IL-1ra) plays an important role in regulating the physiological responses to endogenous IL-1 as it binds the IL-1 receptor, but lacks intrinsic biological activity. IL-1ra is secreted by similar cell types as those which produce IL-1, and in response to similar stimuli (Turnbull and Rivier, 1999). It can therefore also be looked at as a marker for IL-1 activity. IL-1ra is positively controlled by IL-6 and there are findings that IL-1ra is also an acute phase protein (Gabay et al., 1997). IL-1ra, seems to be sensitive to chronic and acute stress and has been found to be raised in individuals with high anxiety levels (Song et al., 1999) and high perceived stress (Maes et al., 1998).
Studies in patients with clinical depression have shown elevated levels of IL-1ra and Il-6 (Maes et al., 1997; Musselman et al., 2001; Seidel et al., 1995). Depression is often associated with higher levels of cortisol (Holsboer, 2000), which seems to contradict the findings of higher cytokine levels in depressed patients. However, within the clinical picture of depression, different subtypes with specific cortisol secretion patterns have been described (Anisman et al., 1999; Gold and Chrousos, 2002). Lower feedback sensitivity of the HPA axis has been shown in major depression (Holsboer, 2000), and this may explain the dysfunction of inflammatory mediators in depression (Licinio and Wong, 1999). It is also possible that individual differences in disturbances of cortisol regulation influence the extent to which elevated levels of inflammatory cytokines are observed.
The secretion of cortisol after stress has been shown to be a reliable marker of psychological stress (Biondi and Picardi, 1999). However, individuals differ in the level of response (Kirschbaum et al., 1995) and in the rate of post-stress recovery (Roy et al., 2001). Gender differences (Kirschbaum et al., 1992), effects of age (Ershler and Keller, 2000; Lutgendorf et al., 1999), personality factors (Pruessner et al., 1997; Van Eck et al., 1996), and mood (Smyth et al., 1998) influence cortisol responses. Persistent cortisol responses without adaptation are thought to be related to susceptibility to infectious disease (Mason, 1991), particularly in individuals with high glucocorticoid sensitivity (Rohleder et al., 2001). On the other hand, blunted cortisol responses to stress could be related to risk of the development of autoimmune disorders (Sternberg, 2001), especially if combined with low glucocorticoid sensitivity (Rohleder et al., 2001). These findings suggest that both high and low cortisol responsivity might be associated with potentially adverse effects.
The aim of the present study was to assess individual differences in salivary cortisol responses to acute mild psychological stress in healthy individuals, and to investigate associations between different types of responses and cytokine levels. We hypothesized that cortisol responses would be inversely associated with proinflammatory cytokines. We also assessed whether cortisol responder types would differ in blood pressure and heart rate stress responses. In addition, we hypothesized that poorer mental health would be related to a stronger cortisol response to stress.
Section snippets
Participants
Data were collected from 109 women and 123 men, part of a sample of 240 drawn from participants in the Whitehall II cohort. The Whitehall II study was set up in 1985 to investigate demographic, psychosocial and biological risk factors for cardiovascular diseases in 10,308 London-based civil servants (Marmot et al., 1991). Participants for this substudy were all white Caucasian and recruited on the following criteria: aged 45–59 years, still based in the London area and not planning to retire
Definition of cortisol responder groups
There was no difference between morning and afternoon testing in cortisol responses, F(1/197)=0.43, p=.51, and the proportion of participants in cortisol responder and non-responder groups was the same for people tested in the morning and afternoon. Analyses were therefore carried out without differentiating between times of testing.
The cortisol stress response in the cortisol responder group averaged 3.45±2.7 nmol/l, compared with a mean decrease of 2.55±2.7 nmol/l in the non-responder group.
Discussion
The increases in cortisol of our participants were relatively small in comparison with those observed in some experimental studies (Biondi and Picardi, 1999; Kirschbaum et al., 1995). The rather mild stressors could explain the small responses observed. Both groups showed a reduction in cortisol from the initial sample to the baseline measurement. The initial sample was obtained prior to inserting the venous cannula, so might reflect an anticipatory response to this procedure. Alternatively,
Acknowledgements
This research was supported by the Medical Research Council, UK. Analyses were also facilitated by the European Scientific Foundation Programme on social variations in health expectancy in Europe. We are grateful to Gonneke Willemsen, Bev Murray, and Natalie Owen for their involvement in data collection. Dr. Kunz-Ebrecht is now in the Department of Social Epidemiology, Institute for Therapy Research, Munich, Germany (e-mail: [email protected]).
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2022, Biological PsychologyCitation Excerpt :Research has shown that attenuated cortisol responses to stress can be maladaptive, with prospective links to CVD risk factors, including obesity and depression (Carroll et al., 2017). This may be explained by the potent anti-inflammatory effects of cortisol under stress (Kunz-Ebrecht et al., 2003), especially given that obesity and depression are characterised by elevated basal levels of inflammation (Ouakinin et al., 2018). Consequently, the findings of Dziembowska et al. (2019) highlight the potential for a link between higher volumes of sedentary behaviour and larger pro-inflammatory responses to stress, but this must remain speculative until future research has tested this.