Original Articles
In humans, serum polyunsaturated fatty acid levels predict the response of proinflammatory cytokines to psychologic stress

https://doi.org/10.1016/S0006-3223(99)00268-1Get rights and content

Abstract

Background: Psychologic stress in humans induces the production of proinflammatory cytokines, such as interferon γ (IFN-γ), tumor necrosis factor α (TNF-α), and interleukin-6 (IL-6), and that of the negative immunoregulatory cytokine, IL-10. An imbalance of ω6 to ω3 polyunsaturated fatty acids (PUFAs) in the peripheral blood causes an overproduction of proinflammatory cytokines. The ω3 PUFAs reduce the production of proinflammatory cytokines.

Methods: This study examines whether an imbalance in ω6 to ω3 PUFAs in human blood predicts a greater production of proinflammatory cytokines in response to psychologic stress. Twenty-seven university students had serum sampled a few weeks before and after as well as 1 day before a difficult oral examination. We determined the ω6 and ω3 fractions in serum phospholipids as well as the ex vivo production of IFN-γ, TNF-α, IL-6, IL-10, and IL-5 by diluted whole blood stimulated with polyclonal activators.

Results: Academic examination stress significantly increased the ex vivo, stimulated production of IFN-γ, TNF-α and IL-10, and the IFN-γ/IL-5 production ratio. Subjects with lower serum ω3 PUFA levels or with a higher ω6/ω3 ratio had significantly greater stress-induced TNF-α and IFN-γ responses than subjects with higher serum ω3 PUFAs and a lower ω6/ω3 ratio, respectively. Subjects with lower serum ω3 PUFA levels or with a higher ω6/ω3 ratio had a significantly higher stress-induced increase in the IFN-γ/IL-5 ratio than the remaining subjects.

Conclusions: Psychologic stress induces a Th-1–like or proinflammatory response in some subjects. An imbalance in the ω6 to ω3 PUFA ratio appears to predispose humans toward an exaggerated Th-1–like response and an increased production of monocytic cytokines, such as TNF-α, in response to psychologic stress. The results suggest that increased ω3 PUFA levels may attenuate the proinflammatory response to psychologic stress.

Introduction

There is now evidence that psychologic stressors may increase the production rate of proinflammatory cytokines, such as interleukin-1 (IL-1), IL-6, tumor necrosis factor α (TNF-α), and interferon γ (IFN-γ), in humans and experimental animals. In rats, electric footshocks, physical restraint, and conditioned aversive stimuli increase the serum concentrations of IL-6 and the expression of IL-6 messenger RNA (mRNA) in the brain LeMay et al 1990, Shizuya et al 1997, Takaki et al 1994, Zhou et al 1993. In the rodent, inescapable shock, immobilization stress, and mild unpredictable and restraint stress produce significant increases in brain IL-1β, IL-1 production by stimulated immunocytes, and IL-1β and IL-1 mRNA levels in the hypothalamus Khlusov et al 1993, Kubera et al 1996, Mekaouche et al 1994, Minami et al 1991, Nguyen et al 1998, Persoons et al 1995, Shintani et al 1995a, Shintani et al 1995b. Academic examination stress in students significantly enhances the stimulated production of proinflammatory cytokines, such as IL-6, TNF-α, and IFN-γ, and that of the negative immunoregulatory cytokine, IL-10 Maes et al 1998a, Maes et al 1998b. High stress perception or greater anxiety levels during the stressful period are related to an increased production of IFN-γ, TNF-α, and IL6, but not IL-10 or IL-5 (Maes et al 1998b).

CD4+ T-cells can be divided into subsets that produce different patterns of cytokines—i.e., Th-1–like CD4+ T-cells produce (among others) IFN-γ, whereas Th-2–like CD4+ T-cells produce IL-5, which stimulates B-cell growth and differentiation. Interleukin 10 is produced by a variety of immunocytes, including monocytes and Th-1–like and Th-2–like T-cells. This negative immunoregulatory cytokine antagonizes Th-1–like cell functions, such as IFN-γ secretion (Cavaillon 1996).

Both ω6 and ω3 polyunsaturated fatty acids (PUFAs) are potent modulators of the inflammatory response system (IRS) and of lymphocytic and monocytic functions (for review, see Maes and Smith 1998). The ω6 PUFAs have proinflammatory capacities: ω6 PUFAs—in particular, C20:4ω6 (arachidonic acid)—are precursors of proinflammatory eicosanoids of the prostaglandin-2 series, such as PGE2(Smith 1991), and increase the production of IL-1, TNF-α and IL-6 Hayashi et al 1998, Meydani et al 1991, Soyland et al 1994, Tashiro et al 1998. The ω3 PUFAs, on the other hand, have anti-inflammatory and immunosuppressive effects. The ω3 PUFAs, such as C20:5ω3 (eicosapentaenoic acid [EPA]), inhibit the synthesis of eicosanoids, such as PGE2, thus antagonizing the effects of ω6 PUFAs (Meydani et al 1991). For example, ω3-rich diets (e.g., fish oil supplements) lead to replacement of C20:4ω6 in the cell membrane by C20:5ω3, which alters the balance of the eicosanoids produced (Calder 1998). Administration of ω3 PUFAs significantly reduces the serum concentrations or the stimulated production of proinflammatory cytokines, such as IL-1, IL-6, TNF-α, and IFN-γ Calder 1998, Caughey et al 1996, Endres et al 1993, Espersen et al 1992, Gallai et al 1995, Meydani et al 1991, Nanji et al 1997, Purasiri et al 1994, Soyland et al 1994, Tashiro et al 1998. Therefore, an imbalance of ω6 to ω3 PUFAs may cause an overproduction of proinflammatory cytokines (Endres et al 1993).

From the literature listed above we hypothesized that the enhanced production of proinflammatory cytokines following psychologic stress in humans could be modulated by baseline serum ω6 and ω3 PUFA levels. We hypothesized that ω6 PUFAs could be positively and ω3 PUFAs negatively related to the production of proinflammatory cytokines following psychologic stress. Our specific aims were to examine the relationships between serum total ω6 and ω3 fractions in serum phospholipids and the stimulated production of the monokines, TNF-α and IL-6; the Th-1–like cytokine, IFN-γ; the Th-2–like cytokine, IL-5; and the negative immunoregulatory cytokine, IL-10, both in baseline conditions and following psychologic stress. Moreover, the stress response to psychologic stressors may entail activation of the hypothalamic–pituitary–adrenal axis (Fukata et al 1993), and subsequent glucocorticoid hormone secretion is considered to be an important messenger responsible for the bidirectional communication between the central nervous system and the immune system (Plata-Salaman, 1991). Glucocorticoids are known to modulate the production of proinflammatory and negative immunoregulatory cytokines (Cavaillon 1996). Therefore, we have adjusted the results of this study for possible effects of plasma cortisol.

Section snippets

Subjects

Twenty-seven university students attending the second year of medical sciences at the Rijksuniversitair Centrum Antwerpen, University of Antwerp participated in this study. The study sample is part of a larger study group on which the effects of psychologic stress on the production of cytokines have been reported Maes et al 1998a, Maes et al 1998b. The age range of the subjects was 19–22 years and there were 12 female students who used contraceptive drugs (monophasic oestroprogestativa), seven

Results

Repeated-measure design ANOVAs showed a significant effect of time on the PSS [F(2,39) = 20.8, p < 10−3], but no significant time × ω3 status interaction [F(2,39) = 0.5, p = .6] and no significant time × ω6 status interaction [F(2,40) = 0.4, p = .7). Dunn’s test (tested at p = .016) showed significantly higher PSS values in the STRESS condition (mean PSS = 29.1 ± 8.2) than in the NEUTRAL PRE (mean PSS = 22.5 ± 5.1) and NEUTRAL POST (mean PSS = 17.5 ± 7.6) conditions.

Table 1shows the ω3, ω6, and

Discussion

Our major finding is that baseline ω6 and ω3 PUFA levels and their ω6/ω3 ratio are related to the ex vivo, stimulated production of TNF-α and IFN-γ and to the IFN-γ/IL-5 production ratio following psychologic stress. Our findings that the stimulated production of IFN-γ and TNF-α following psychologic stress is significantly greater in subjects with lower ω3 PUFA levels than in those with higher ω3 PUFA levels is in agreement with the well-known anti-inflammatory or immunosuppressive activities

Acknowledgements

The research was supported in part by the Fund for Scientific Research, Vlaanderen (FWO); the Clinical Research Center for Mental Health (CRC-MH), Antwerp, Belgium; and the Staglin Investigator Award to Dr. M. Maes (National Alliance for Research on Schizophrenia and Depression, USA). The assistance of Mrs. M. Maes is greatly appreciated.

References (62)

  • E. Lagging et al.

    Cytokine production in PBMC from allergics and non-allergics following in vitro allergen stimulation

    Immunol Lett

    (1998)
  • L.G. LeMay et al.

    The effects of psychological stress on plasma interleukin-6 activity in rats

    Physiol Behav

    (1990)
  • M. Maes et al.

    Fatty acid composition in cholesteryl esters and phospholipids in depression

    Psychiatry Res

    (1999)
  • M. Maes et al.

    Fatty acid composition in major depressionDecreased ω3 fractions in cholesteryl esters and increased C20:4ω6/C20:5ω3 ratio in cholesteryl esters and phospholipids

    J Affect Disord

    (1996)
  • M. Maes et al.

    Anti-inflammatory effects of antidepressants (fluoxetine, trazodone, clomipramine)Increased production of interleukin-10 and suppressed production of interferon-gamma

    Neuropsychopharmacology

    (1999)
  • M. Maes et al.

    The effects of psychological stress on humansIncreased production of pro-inflammatory cytokines and a Th1-like response in stress-induced anxiety

    Cytokine

    (1998)
  • S.N. Meydani et al.

    Oral (n-3) fatty acid supplementation suppresses cytokine production and lymphocyte proliferationComparison between young and older women

    J Nutr

    (1991)
  • M. Minami et al.

    Immobilization stress induces interleukin-1 beta mRNA in the rat hypothalamus

    Neurosci Lett

    (1991)
  • F.A.J. Muskiet et al.

    Capillary gas chromatographic profiling of total long-chain fatty acids and cholesterol in biological materials

    J Chromatogr

    (1983)
  • A.A. Nanji et al.

    Dietary saturated fatty acids down-regulate cyclooxygenase-2 and tumor necrosis factor alfa and reverse fibrosis in alcohol-induced liver disease in the rat

    Hepatology

    (1997)
  • M. Peet et al.

    Depletion of omega-3 fatty acid levels in red blood cell membranes of depressive patients

    Biol Psychiatry

    (1998)
  • C.R. Plata-Salaman

    Immunoregulators in the nervous system

    Neurosci Biobehav Rev

    (1991)
  • R.S. Smith

    The macrophage theory of depression

    Med Hypotheses

    (1991)
  • T. Tashiro et al.

    n-3 versus n-6 polyunsaturated fatty acids in critical illness

    Nutrition

    (1998)
  • L.L. Williams et al.

    Quantitative association between altered plasma esterified omega-6 fatty acid proportions and psychological stress

    Prostaglandins Leukot Essent Fatty Acids

    (1992)
  • P.F. Zangerle et al.

    Direct stimulation of cytokines (IL-1 beta, TNF-alpha, IL-6, IL-2, IFN-gamma and GM-CSF) in whole bloodII. Application to rheumatoid arthritis and osteoarthritis

    Cytokine

    (1992)
  • K.H. Baumann et al.

    Dietary omega-3, omega-6, and omega-9 unsaturated fatty acids and growth factor and cytokine gene expression in unstimulated and stimulated monocytesA randomized volunteer study

    Arterioscler Thromb Vasc Biol

    (1999)
  • P.C. Calder

    Immunoregulatory and anti-inflammatory effects of n-3 polyunsaturated fatty acids

    Braz J Med Biol Res

    (1998)
  • J.-M. Cavaillon

    Les Cytokines

    (1996)
  • S. Cohen et al.

    A global measure of perceived stress

    J Health Soc Behav

    (1983)
  • S. Endres et al.

    Dietary supplementation with n-3 fatty acids suppresses interleukin-2 production and mononuclear cell proliferation

    J Leukoc Biol

    (1993)
  • Cited by (108)

    • Antenatal depressive symptoms are strongly predicted by the severity of pre-menstrual syndrome: results of partial least squares analysis

      2023, International Journal of Clinical and Health Psychology
      Citation Excerpt :

      It is indeed well-known that even mild psychological stressors induce and immune-inflammatory response as well as T cell activation (Maes et al., 1998; Maes et al., 1999). It is interesting to note that these stress effects on the cytokine network are pronounced in subjects with lowered levels of omega-3 polyunsaturated fatty acids (Maes et al., 2000) which is known to predict depressive symptoms in the perinatal period (De Vriese et al., 2003). Consequently, the main hypothesis is that ACE-induced immune responsivity contributes to PMS and perinatal depression, and that the sex-hormone alterations leading to PMS (Roomruangwong & Maes, 2021) aggravate the immune response thereby aggravating perinatal depression.

    • Relationships between inflammatory markers and suicide risk status in major depression

      2021, Journal of Psychiatric Research
      Citation Excerpt :

      As expected from previous studies (Keilp et al., 2006; Oquendo et al., 2004), we also found higher trait aggression in suicide attempters; however, we found no relationship between aggression and the biological markers that we studied. DHA has well-established anti-inflammatory properties, and low DHA levels have been consistently associated with pro-inflammatory states in animal (McNamara et al., 2010) and human studies (Ferrucci et al., 2006; Maes et al., 2000; Micallef et al., 2009). Furthermore, DHA metabolites (SPMs), namely resolvins, protectins and maresins, actively stimulate the inflammation resolution process (reviewed in (Joffre et al., 2019; Serhan, 2014)).

    • Evidence-Based Nutrition and Clinical Evidence of Bioactive Foods in Human Health and Disease

      2021, Evidence-Based Nutrition and Clinical Evidence of Bioactive Foods in Human Health and Disease
    • Docosahexaenoic acid,22:6n-3: Its roles in the structure and function of the brain

      2019, International Journal of Developmental Neuroscience
    View all citing articles on Scopus
    View full text