Transient responses of inflammatory cytokines in acute stress
Introduction
Recent studies in psychoneuroimmunology have focused on the effects of stress on pro-inflammatory cytokines in peripheral blood and the brain (Chen and Reichlin, 1999, Dantzer et al., 2008). Pro-inflammatory cytokines such as interleukin-1beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α) are defined as cytokines promoting systemic inflammation by bringing immune cells to the site of infection or injury (Baumann and Gauldie, 1994). They play important roles in eliminating invading virus and bacteria and conserving energy in the immune system (Black, 2006). Furthermore, they can work as mediators in bi-directional immune-brain communication since peripherally increased levels of pro-inflammatory cytokines can affect the brain and induce behavioral changes such as depression, hyperalgesia, and the memory deficit called “sickness response” (Maier, 2003). Although previous studies (Brydon et al., 2005, Steptoe et al., 2007) demonstrated that pro-inflammatory cytokines increased after an acute psychological stress task, the precise mechanism of the increase is still unclear.
According to a meta-analysis of human studies examining the effects of acute psychological stress tasks on pro-inflammatory cytokines, especially an increased level of IL-6, at 90 min following acute psychological stress tasks is the most consistent result (Steptoe et al., 2007). Moreover, previous studies suggested essential roles of other cytokines such as IL-1β in acute stress responses (Ackerman et al., 1998, Altemus et al., 2001, Heinz et al., 2003). IL-1β is mainly secreted by monocytes and macrophages and is especially related to fever (Delaleu and Bickel, 2004). Since previous findings indicated that IL-1β increased the expression of adhesion factors on endothelial cells to enable the transmigration of leukocytes, the cells that fight pathogens, to sites of infection, IL-1β played an important role in eliminating virus and bacteria during infections (Dinarello, 1996). Furthermore, animal studies demonstrated that peripherally produced IL-1β induced the central production of IL-1β, which in turn activated the responses of the hypothalamus–pituitary–adrenal cortex (HPA) axis to stress (Maier, 2003). Based on these findings, Yirmiya et al. (2002) suggested that the secretion of IL-1β should be considered a primary mechanism enabling the satisfaction of stress-associated metabolic and behavioral demands during an acute stress situation (e.g., fight or flight).
Despite such essential roles, few studies have examined the effects of acute psychological stress tasks on the IL-1β level, and the results that have been reported are inconsistent. For example, Heinz et al. (2003) reported increase of the IL-1β level immediately after a 2 h interview. In addition, Altemus et al. (2001) observed elevation of the IL-1β level at 40 min after the Trier Social Stress Test (TSST). However, they did not measure IL-1β immediately after the TSST, but 40 min after. Dugue et al. (1993), however, used a 10 min Stroop task and found no responses in IL-1β. It is possible that differences of tasks, task durations, and time points of measurement among the studies are why consistent results were not obtained. Similarly, although TNF-α and interferon-gamma (IFN-γ), which are also classified as pro-inflammatory cytokines, were suggested to play important roles in stress responses, the effects of acute stress on them are also inconsistent, possibly due to different procedures used among previous studies (Owen and Steptoe, 2003, Miller et al., 2005, Heesen et al., 2005, Buske-Kirschbaum et al., 2007). Thus, to elucidate how pro-inflammatory cytokines are influenced by acute stress, it is necessary to employ a standardized acute stress task and assess the temporal variation of IL-1β, IL-6, TNF-α, and IFN-γ as well as other physiological stress responses in the same experimental setting.
The present study aimed to examine temporal characteristics of changes of pro-inflammatory cytokines under acute stress using the TSST, which is a well-defined standardized acute psychological stress task (Kirschbaum et al., 1993, Dickerson and Kemeny, 2004). Furthermore, associations between transient variations of pro-inflammatory cytokines and sickness responses were also examined. Specifically, associations between transient variations of pro-inflammatory cytokines and self-reports of the subjective intensity of stress and affective states were examined. To accomplish these aims, plasma concentrations of several pro-inflammatory cytokines (IL-1β, IL-2, IL-6, IL-12, TNF-α, and IFN-γ) were measured before and after the TSST, and every 30 min during a post-stress rest period (30, 60, and 90 min after the completion of the TSST). To verify the present experimental manipulation, the proportions of blood lymphocyte subsets (CD3+CD4+ helper T cell, CD16+CD56+ natural killer (NK) cell), plasma cortisol concentration, and heart rate (HR) were also assessed because these responses have been observed repeatedly and confirmed as typical acute stress responses in previous studies (Benschop et al., 1996, Willemsen et al., 2002, Isowa et al., 2004, Isowa et al., 2006).
Section snippets
Participants
Sixteen Japanese male undergraduates at Nagoya University (age range 18–26 years; mean = 21.1; S.D. = 2.4) participated. None of the participants were suffering from any chronic illnesses and none were taking medications known to influence immunity. A summary of demographic characteristics of the participants is presented in Table 1. The participants were advised not to smoke and drink alcohol during any days when they participated in the experiments. All participants signed an informed consent to
ANCOVAs with baseline levels of psychological measure
Parallelism tests of regression line yielded no significance for all physiological measures after adjustment with all psychological measures as covariates. For all physiological measures, significant tests of regression line with intensity of stress, pleasantness, anxiety, and irritation revealed significance. Therefore, for each physiological measure, we firstly conducted a repeated—measures ANOVA, and then, we examined influences of background psychological factors on the effects of the
Discussion
The present results showed that HR, cortisol, the proportion of NK cells, and perceived intensity of stress increased immediately after the TSST. The combination of these physiological and psychological responses under acute stress was typically observed in various previous studies (Isowa et al., 2004, Isowa et al., 2006, Het and Wolf, 2007). Therefore, it was confirmed that the TSST used in the present study provided a sufficiently robust acute stressor for the experimental procedure.
The main
Conflict of interest
All authors declare that there are no conflicts of interest.
Acknowledgments
This work was supported by a Grant-in-Aid for Students Research in Graduate School of Environmental Studies, Nagoya University. Portions of the present study were presented at the 67th Annual Scientific Meeting of the Organization for American Psychosomatic Society (Chicago, March 2009).
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2021, PsychoneuroendocrinologyCitation Excerpt :Finally, we distinguish between cytokines that are markers of or which have pro- and anti-inflammatory functions. In the context of acute stress, anti-inflammatory cytokines rise in response to increases in proinflammatory cytokines to regulate/limit inflammation (Elenkov and Chrousos, 2002; Opal and DePalo, 2000); however, perceived stress and chronic stress have been linked with higher levels of both pro- and anti-inflammatory cytokines (Miller et al., 2009; Yamakawa et al., 2009). The present review includes studies that utilized diverse inflammatory markers, which we differentiate in three ways: proinflammatory markers, anti-inflammatory cytokines, and TH-1 cytokines.