Natural killer cell and proinflammatory cytokine responses to mental stress: associations with heart rate and heart rate variability

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Abstract

Associations between natural killer (NK) cell, proinflammatory cytokine stress responsivity, and cardiac autonomic responses (indexed by heart rate and heart rate variability) were assessed in 211 middle-aged men and women. Blood was drawn at baseline, immediately following color–word interference and mirror tracing tasks for the assessment of NK cell numbers, and 45 min post-stress for assessing plasma interleukin 6 (IL-6) and tumor necrosis factor alpha (TNFα) responses. Heart rate variability was measured as the root mean square of successive differences (RMSSD) in R–R intervals. Increases in NK cell counts following stress were positively associated with heart rate responses independently of age, sex, socioeconomic status, smoking, and change in hematocrit. Heart rate 45 min post-stress was positively associated with plasma IL-6 post-stress, and with TNFα changes from baseline, independently of covariates. No relationship between immune responses and heart rate variability was observed. We conclude that individual differences in sympathetically-driven cardiac stress responses are associated with NK and proinflammatory cytokine responses to psychological stress.

Introduction

The immune system is highly sensitive to acute psychological stress, with rapid changes in numbers of circulating natural killer (NK) cells and other lymphocytes, increased NK cell cytotoxicity, and reductions in mitogen-induced lymphocyte proliferation (Zorrilla et al., 2001). Increases in plasma levels of proinflammatory cytokines such as interleukin 6 (IL-6) and tumor necrosis factor alpha (TNFα) have also been described, although findings have been inconsistent (Ackerman et al., 1998, Dugué et al., 1993). Cytokine responses evolve more slowly than do other immune changes, so may not be observed in studies that are limited to immediate post-stress blood sampling (Steptoe et al., 2001).

It is probable that acute immune stress responses are mediated in part by sympathoadrenal activation. Primary and secondary lymphoid tissues are extensively innervated by the sympathetic nervous system (Elenkov et al., 2000). Catecholamines play a central role in lymphocyte migration, circulation, and trafficking (Benschop et al., 1996). NK cell counts are particularly sensitive to infusions of catecholamines, while T and B cell counts are less affected (Schedlowski et al., 1996). The effects of sympathoadrenal activity on inflammatory cytokines is more varied, with evidence of inhibition of plasma levels of TNFα (Elenkov et al., 2000, Goebel et al., 2000). However, Mohamed-Ali et al. (2001) have demonstrated that increases in IL-6 follow isoproterenol infusion in humans.

Positive associations between increases in norepinephrine and immune responses to stress have been described (Cohen et al., 2000, Mills et al., 1995a), but there are limitations to venous catecholamine sampling for the assessment of systemic sympathoadrenal activity (Hjemdahl, 1993). Methods such as microneurographic measurement of activity in sympathetic nerves (Wallin, 1981), and assessments of labeled norepinephine spillover (Esler et al., 1989) provide direct evidence, but are difficult to employ in larger scale studies. Cardiovascular variables are, therefore, frequently utilized as markers of sympathoadrenal activation. Systolic blood pressure, heart rate, and pre-ejection period all increase with sympathetic stimulation. Blood pressure is less valuable as a marker in this context than the other measures, since pressure responses tend to be preserved by alternative haemodynamic pathways when sympathetic stimulation is interrupted. Thus blood pressure stress responses are generally unaffected by β-adrenergic blockade, while heart rate responses are attenuated (Freyschuss et al., 1988). Lenders et al. (1988) found that heart rate responses to mental stress were reduced in adrenalectomised compared with intact participants, while pressure responses were no different. Julius (1988) has argued that there is haemodynamic plasticity in responses to autonomic activation, and that the cardiovascular system regulates the circulation to achieve blood pressure levels through alternative mechanisms if some are unavailable.

There is substantial evidence from laboratory studies that heart rate responses are associated with stress-induced increases in NK cell counts and activity (Benschop et al., 1998, Cohen et al., 2000, Manuck et al., 1991, Sgoutas-Emch et al., 1994). Conversely, NK cell mobilization and other immune responses to stress are reduced following α and β-adrenergic blockade (Bachen et al., 1992, Benschop et al., 1994). There is little evidence concerning the cardiovascular correlates of inflammatory cytokine stress responses. However, we recently showed in a small study that IL-6 sampled 45 min post-stress and TNFα sampled 2 h post-stress were associated with cardiovascular responses (Steptoe et al., 2001). The first aim of this study was, therefore, to assess associations between heart rate and IL-6 and TNFα stress responses in a large sample of middle-aged men and women. Since cytokine responses to stress may take time to emerge, they were assessed from blood sampled 45 min post-stress. We also analyzed the relationship between heart rate and acute NK cell responses, as evidence from this age group is limited at present.

Heart rate is not of course a simple index of sympathetic activation, since it is regulated by the balance between sympathetic and parasympathetic pathways. Heart rate variability can, with caution, be regarded as an indicator of cardiac vagal control (Berntson et al., 1997). Consequently, we assessed heart rate variability as well as heart rate responses, reasoning that the combination would permit conclusions to be drawn about the relative importance of sympathetic and vagal influences on stress-induced immune changes. A number of other factors are potentially relevant to changes in plasma cytokines and NK cell counts, including hematocrit (Marsland et al., 1997), age, body mass, abdominal obesity, smoking, and method of blood sampling (Haack et al., 2002), so these were also included in the analyses.

These analyses were carried out on data from a study designed to assess psychobiological factors related to socioeconomic status. The responses to stress of heart rate, heart rate variability, cytokines, and NK cell counts in relation to socioeconomic status and sex have been described elsewhere (Steptoe et al., 2002a, Steptoe et al., 2002b).

Section snippets

Participants

These analyses were carried out on 211 of the 240 men and women who took part in mental stress testing as part of a larger study of psychobiological processes related to socioeconomic status. They were all members of the Whitehall II epidemiological cohort, a sample of 10 308 London-based civil servants recruited in 1985–1988 when aged 35–55 years to investigate demographic, psychosocial and biological risk factors for CHD (Marmot et al., 1991). Participants were of Caucasian origin, aged 45–59

Results

The background characteristics of the men and women in this study are summarized in Table 1. Men were slightly older on average than women (F(1,209)=5.44, P=021). There were no sex differences in the distribution of participants by grade of employment, cigarette smoking, or body mass index. Waist/hip ratios were greater in men than women (F(1,209)=73.8, P<0.001), as is generally found in the literature.

The heart rate, heart rate variability, NK cell and inflammatory cytokine responses to mental

Discussion

The results of these analyses indicate that NK cell and inflammatory cytokine responses to psychological stress were associated with heart rate but not heart rate variability. We categorized heart rate and heart rate variability into quartiles rather than using a continuous regression approach, so as to be able to investigate effects on a common metric. However, the results were similar when regression methods were used. No relationships between resting heart rate and baseline NK cell counts or

Acknowledgements

This research was supported by the Medical Research Council, UK. We are grateful to Sabine Kunz-Ebrecht, Pamela J. Feldman, Gonneke Willemsen, and Bev Murray for their assistance in data collection. The cytokine analyses were carried out by Vidya Mohamed-Ali (Department of Medicine, University College London), and the NK cell analyses in the Department of Biochemistry and Immunology, St. George's Hospital Medical School, London.

References (54)

  • P.J. Mills et al.

    Lymphocyte subset redistribution in response to acute experimental stress: effects of gender, ethnicity, hypertension, and the sympathetic nervous system

    Brain, Behavior, and Immunity

    (1995)
  • P.J. Mills et al.

    Enumerative immune changes following acute stress: effect of the menstrual cycle

    Brain, Behavior, and Immunity

    (1995)
  • A. Steptoe et al.

    Inflammatory cytokines, socioeconomic status, and acute stress responsivity

    Brian, Behavior, and Immunity

    (2002)
  • E.P. Zorrilla et al.

    The relationship of depression and stressors to immunological assays: a meta-analytic review

    Brain, Behavior, and Immunity

    (2001)
  • K.D. Ackerman et al.

    Stressor-induced alteration of cytokine production in multiple sclerosis patients and controls

    Psychosomatic Medicine

    (1998)
  • E.A. Bachen et al.

    Lymphocyte subset and cellular immune responses to a brief experimental stressor

    Psychosomatic Medicine

    (1992)
  • R.J. Benschop et al.

    Effects of beta-adrenergic blockade on immunologic and cardiovascular changes induced by mental stress

    Circulation

    (1994)
  • R.J. Benschop et al.

    Cardiovascular and immune responses to acute psychological stress in young and old women: a meta-analysis

    Psychosomatic Medicine

    (1998)
  • G.G. Berntson et al.

    Heart rate variability: origins, methods, and interpretive caveats

    Psychophysiology

    (1997)
  • L.M. Biasucci et al.

    Increasing levels of interleukin (IL)-1Ra and IL-6 during the first 2 days of hospitalization in unstable angina are associated with increased risk of in-hospital coronary events

    Circulation

    (1999)
  • P. Castiglioni et al.

    Broad-band spectral analysis of 24 h continuous finger blood pressure: comparison with intra-arterial recordings

    Clinical Science

    (1999)
  • S. Cohen et al.

    The stability of and intercorrelations among cardiovascular, immune, endocrine, and psychological reactivity

    Annals of Behavioral Medicine

    (2000)
  • A.N. Dentino et al.

    Association of interleukin-6 and other biologic variables with depression in older people living in the community

    Journal of the American Geriatric Society

    (1999)
  • B. Dugué et al.

    Effects of psychological stress on plasma interleukins-1 beta and 6, C-reactive protein, tumor necrosis factor alpha, anti-diuretic hormone and serum cortisol

    Scandinavian Journal of Clinical and Laboratory Investigation

    (1993)
  • B. Dugué et al.

    The driving license examination as a stress model: effects on blood picture, serum cortisol and the production of interleukins in man

    Life Sciences

    (2001)
  • I.J. Elenkov et al.

    The sympathetic nerve—an integrative interface between two supersystems: the brain and the immune system

    Pharmacological Reviews

    (2000)
  • L. Ferrucci et al.

    Serum IL-6 level and the development of disability in older persons

    Journal of the American Geriatric Society

    (1999)
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