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The effects of acute psychological stress on circulating inflammatory factors in humans: A review and meta-analysis

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Abstract

Stress influences circulating inflammatory markers, and these effects may mediate the influence of psychosocial factors on cardiovascular risk and other conditions such as psoriasis and rheumatoid arthritis. Inflammatory responses can be investigated under controlled experimental conditions in humans, and evidence is beginning to emerge showing that circulating inflammatory factors respond to acute psychological stress under laboratory conditions. However, research published to date has varied greatly in the composition of study groups, the timing of samples, assay methods, and the type of challenge imposed. The purpose of this review is to synthesize existing data using meta-analytic techniques. Thirty studies met inclusion criteria. Results showed robust effects for increased levels of circulating IL-6 (r = 0.19, p = 0.001) and IL-1β (r = 0.58, p < 0.001) following acute stress, and marginal effects for CRP (r = 0.12, p = 0.088). The effects of stress on stimulated cytokine production were less consistent. Significant variation in the inflammatory response was also related to the health status of participants and the timing of post-stress samples. A number of psychobiological mechanisms may underlie responses, including stress-induced reductions in plasma volume, upregulation of synthesis, or enlargement of the cell pool contributing to synthesis. The acute stress-induced inflammatory response may have implications for future health, and has become an important topic of psychoneuroimmunological research.

Introduction

It is well established in animal and human research that the immune system responds acutely to psychological stress. Many studies have documented changes in the number and proportion of circulating T and B cells, alterations in natural killer cell numbers and cytotoxicity, and impairment of functional responses such as mitogen-induced cell proliferation (Zorrilla et al., 2001, Segerstrom and Miller, 2004). More recently, research has focused on the link between stress or other psychosocial factors and markers of inflammation. Cross-sectional studies have shown associations between psychosocial factors such as low social economic status (SES), chronic work stress, caregiver strain, early life adversity, hostility and social isolation, and circulating levels of C-reactive protein, interleukin (IL)-6 and tumor necrosis factor (TNF) α (Alley et al., 2006, Danese et al., 2007, Hemingway et al., 2003, Koster et al., 2006, Loucks et al., 2006a, Loucks et al., 2006b, Suarez et al., 2004, Wright et al., 2004). There is an extensive though inconsistent literature relating depression with inflammatory markers (Ford and Erlinger, 2004, Irwin, 2006, Penninx et al., 2003). Longitudinally, caregiver stress predicts an accelerated age-related increase in IL-6 (Kiecolt-Glaser et al., 2003). These associations may be relevant to understanding how psychosocial factors influenced disease risk and prognosis. Elevated C-reactive protein predicts hypertension (Sesso et al., 2003), future coronary heart disease (CHD) and cardiac mortality (Albert et al., 2002, Danesh et al., 2004, Pai et al., 2004). The concentrations of IL-6 and TNF-α are also associated with hypertension, subclinical atherosclerosis and with CHD (Amar et al., 2006, Cesari et al., 2003, Lindmark et al., 2001, Niskanen et al., 2004, Ridker et al., 2000). Heightened levels of C-reactive protein and IL-6 predict mortality in the elderly independently of conventional risk factors (Reuben et al., 2002). Inflammatory processes are implicated in obesity (Guest et al., 2007), sleep disorders (Opp et al., 2007), frailty in older age (Ferrucci et al., 1999), posttraumatic stress disorder (von Känel et al., 2006a) and other conditions.

Evidence is beginning to emerge showing that inflammatory factors respond to acute psychological stress under laboratory conditions. Laboratory studies have the advantage of allowing biological responses to be investigated under standardized conditions, taking account of potential confounders that are difficult to control in population studies. Research published to date has varied greatly in the composition of study groups, the timing of samples, assay methods, and the type of challenge imposed. There has been a substantial growth of research on acute responses since the literature was reviewed by Segerstrom and Miller (2004). The purpose of this review is to synthesize existing data using meta-analytic techniques to address the following questions:

  • 1.

    What markers of inflammation are sensitive to acute psychological stress in humans?

  • 2.

    What is the time course of responses, and how soon do they appear following stress exposure?

  • 3.

    Are there differences in response related to factors such as gender, age, health status, or to the nature of the acute challenge?

  • 4.

    What mechanisms might be involved?

Section snippets

Markers of inflammation

A number of inflammatory markers have been studied in relation to psychological stress. These include markers that are predominantly pro-inflammatory (IL-1β, IL-2, IL-8, TNF-α, C-reactive protein, interferon [IFN-γ]), those that are anti-inflammatory (IL-4, IL-10), and IL-6 which is considered to have both pro- and anti-inflammatory properties. Cytokines are signaling proteins expressed in a number of tissues, notably monocytes/macrophages, vascular endothelial cells, adipose tissue, and

Search strategy and inclusion criteria

We conducted a systematic review of relevant literature using the MEDLINE database and scrutiny of reference lists from relevant reviews and articles. Eligibility for inclusion was independently determined by two authors. Criteria for inclusion were full peer reviewed journal articles in English language, which examined circulating inflammatory cytokine and C-reactive protein responses to a psychological laboratory stress task in human volunteers. Responses to acute physical exercise were not

Summary of studies

Thirty studies (1749 participants) met the inclusion criteria and are summarized in Table 1, Table 2. Eleven studies examined clinical groups consisting of patients with psoriasis vulgaris, multiple sclerosis, rheumatoid arthritis, clinical depression, chronic fatigue syndrome, cancer survivors, and coronary artery disease. A wide range of cytokines was examined including TNF-α, IFN-γ, IL-1β, IL-1ra, IL-2, IL-4, IL-6, IL-8, IL-10, and in addition C-reactive protein. Interleukin-6 was the most

Mechanisms underlying acute changes in inflammatory markers

Different processes are likely to be responsible for changes in circulating levels and in in vitro responses to immunogens. In the former, factors associated with acute stress directly stimulate changes in levels, while in the in vitro studies, acute stress mediators can only exert a modulating effect on activation by LPS or other substances. In vitro studies assess cytokine production by circulating white blood cells alone, whereas other tissues may contribute to plasma or serum responses.

Control groups

It is striking that few studies of acute inflammatory responses have included no stress control groups. Investigators appear to have assumed that the levels of inflammatory markers are stable in the absent of stimulation. However, there are two reasons why this is not necessary the case. First, a number of inflammatory markers show diurnal variation. Pronounced circadian changes have been recorded in IL-1β, IL-6 and TNF-α (Opp et al., 2007, Vgontzas et al., 2005), although C-reactive protein is

Clinical significance of acute cytokine and C-reactive protein responses

The rationale for studying acute inflammatory responses to stress in the laboratory is that physiological changes can be investigated in detail under controlled conditions, reducing many of the sources of bias and individual differences that might be present with measures in the field or clinic (Steptoe, 2005). Experimental designs can be used with randomization to different conditions, while sophisticated autonomic measurement and handling of blood samples may provide insight into underlying

Conclusions and directions for future research

Our meta-analysis suggests a modest increase in circulating inflammatory markers following laboratory-induced psychological stress. Factors such as gender, health status, timing of post-stress samples, and method of measurement may impact on the response, although the data are equivocal at present. Most research has been carried out with IL-6, TNF-α, IL-1β, and C-reactive protein, and there is limited information about other pro- and anti-inflammatory cytokines. Most studies have been small

Acknowledgments

This research was supported by the British Heart Foundation. We thank the authors who kindly provided the data necessary for our meta-analysis, and an unnamed reviewer for helpful conceptual comments.

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