Original ArticlesIn humans, serum polyunsaturated fatty acid levels predict the response of proinflammatory cytokines 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.
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