Objective: To investigate whether the daily intake of red wine (RW) at a dose which inversely correlates with cardiovascular disease (CVD) risk modulates immune functions in healthy men.
Design: Randomized single-blind trial with four intervention periods.
Setting: The Institute of Nutritional Physiology, Federal Research Centre for Nutrition, Karlsruhe, Germany.
Subjects: A total of 24 healthy males with moderate alcohol consumption patterns were recruited and all completed the study.
Interventions: Participants consumed 500 ml of RW (12% ethanol (ETOH)) or 500 ml of a 12% ETOH dilution per day for a period of 2 weeks. To control the potential effects of RW polyphenols, accordingly 500 ml/day of dealcoholized red wine (DRW) and of red grape juice (RGJ) were given. The following immune parameters were measured before beverage consumption and at 1 and 2 weeks following beverage consumption: phagocytic activity of neutrophils and monocytes, production of tumor necrosis factor-alpha (TNFα), interleukin-2 and -4, transforming growth factor-β, TNFα mRNA, lymphocyte proliferation, lytic activity of natural killer cells, and percentage of apoptotic lymphocytes.
Results: Consumption of a moderate volume of alcohol with RW and with a 12% ETOH dilution had no effect on immune functions in healthy males. Consumption of polyphenol-rich beverages (DRW and RGJ) did not affect immunity-related parameters.
Conclusions: Daily moderate consumption of alcohol and of RW for 2 weeks at doses which inversely correlate with CVD risk has no adverse effects on human immune cell functions. Polyphenol-rich beverages such as RGJ and DRW further do not suppress immune responses in healthy men.
Sponsorship: The Federal Ministry of Consumer Protection, Food, and Agriculture, Germany.
Moderate consumption of alcohol is inversely associated with cardiovascular disease (CVD) risk (Renaud et al, 1998; Gaziano et al, 1999; Rimm et al, 1999; Gronbaek et al, 2000). In addition, moderate intake of alcohol (up to three drinks) or wine may strengthen the immune response toward different types of viruses. For example, in nonsmokers intentionally exposed to rhinoviruses, alcohol consumption was associated with a decreased risk of common cold (Cohen et al, 1993). Epidemiological data from a recent prospective cohort study revealed that total alcohol intake as well as beer and spirit consumptions were not related to the occurrence of common cold, whereas moderate consumption of wine was inversely associated with the risk of common cold. The association was stronger for red wine (RW) when compared with white wine (Takkouche et al, 2002), which suggests that specific polyphenols in RW may contribute to the observed reduction in common cold risk. Recently, in an animal study it was shown that ethanol (ETOH) intake with RW (corresponding to an intake of 360 ml of RW in humans) produced no changes in blood lymphocyte and NK cell numbers, while a similar intake of ETOH alone reduced the percentage of these cells (Percival & Sims, 2000). Based on these data, one may speculate that polyphenols in RW protect from potential adverse effects of ethanol on the immune system.
Besides its beneficial effect on CVD risk, alcohol consumption at a level of more than three drinks per day is associated with an increased all-cause mortality (Ellison, 2002). Chronic ethanol abuse is known to result in specific defects in innate and acquired immunity and may increase host susceptibility to infections (Watzl & Watson, 1992; Nelson & Kolls, 2002). In a case–control study of patients with community-acquired pneumonia, alcohol intake was identified as a risk factor. High-alcohol intake patients showed a higher incidence of pneumonia and more severe clinical symptoms than patients with a low alcohol intake (Fernandez-Sola et al, 1995). ETOH in vitro suppresses significantly the production of pro-inflammatory cytokines such as tumor necrosis factor-α (TNFα) by human peripheral blood mononuclear cells (PBMCs) (Watzl & Watson, 1993; Szabo et al, 1996). Chronic alcohol intake, however, results in an enhanced response of proinflammatory cytokines (Nelson & Kolls, 2002). Moreover, ETOH exposure of polymorphonuclear neutrophilic granulocytes (PNG) and monocytes in vitro and in vivo inhibits phagocytosis (Stoltz et al, 1999) and decreases their capacity to produce reactive oxygen species during the oxidative burst (Patel et al, 1996; Szabo, 1999).
Alcohol consumption and its subsequent metabolism in the liver generate reactive oxygen species, which interfere with various immune cell functions. Phenolic antioxidants in RW may scavenge reactive oxygen species and thereby protect the host against impairment of immune cell functions by ETOH intake. RW consumption delivers polyphenols such as the flavonoids with strong in vitro and in vivo antioxidant (Wang et al, 1997; Casalini et al, 1999; Lodovici et al, 2001) and immunomodulatory effects (Middleton et al, 2000). Despite this, the immunological effects of flavonoids in humans have not yet been studied. Most polyphenol studies so far were done in in vitro systems demonstrating that flavonoids suppress a variety of immune functions including lymphocyte proliferation, lytic activity of NK cells, and cytokine secretion (Middleton et al, 2000).
The objective of this study was first to investigate whether daily consumption of a moderate volume of RW modulates immune functions in healthy men during a period of 2 weeks. The second aim was to investigate whether polyphenols in RW with their antioxidative and immunomodulatory potential induce changes in immune functions that differ from those induced by the consumption of a 12% ETOH beverage. To broadly assess changes in immune functions, we have measured a large range of immune parameters.
Subjects and methods
In all, 24 nonsmoking men with moderate alcohol consumption patterns (≤80 g ETOH/week) and with normal body weight were recruited for the study. All subjects were in good medical health as determined by a screening history and medical examination. None were taking vitamin supplements or medications 2 months before or during the study. The study was approved by the Medical Ethical Committee of the Landesärztekammer Baden-Württemberg and all participants gave their consent in writing.
This study was a randomized crossover study of four experimental treatments, each lasting 14 days. During the experimental treatments, subjects were randomly assigned to consume 500 ml/day of RW (12% ETOH v/v), dealcoholized red wine (DRW), red grape juice (RGJ), and ETOH (12% ethanol v/v), with a wash-out period of 1 week between each experimental treatment. Subjects were instructed to drink the beverages with their main meals. During the study period, subjects adhered to their usual diets, but were instructed to avoid alcohol-containing beverages and food products rich in anthocyanins or polyphenols (Bub et al, 2001).
RW (variety Lemberger) and RGJ (variety Lemberger) grown in the same vineyard were obtained from the State Winery Weinsberg (Baden-Württemberg, Germany). Dealcoholization of the RW was achieved by a vacuum rectification process (Centre for dealcoholization EAZ Petershans GmbH, Waiblingen, Germany). The total anthocyanin (mg/l) and total catechin ((+)-catechin and (−)-epicatechin, mg/l) contents were 171.1 and 63.4 (RW), 144.8 and 47.0 (DRW), and 338.6 and 64.3 (RGJ), respectively. The resveratrol content (mg/l) was 4.94 (RW), 5.15 (DRW), and 3.75 (RGJ) (Bub et al, 2001). The 12% ethanol beverage was prepared from vodka.
Collection and preparation of blood samples
Fasting venous blood samples were collected once a week between 7:00 and 10:00. Blood was drawn from an antecubital vein into prechilled tubes containing Li-heparin (Monovette-Sarstedt, Nümbrecht, Germany) and immediately placed on ice in the dark. Plasma was collected after centrifugation at 1500 × g for 10 min at 4°C. PBMC were prepared as described earlier (Watzl et al, 2000).
PBMC at 1 × 109 cells/l in a medium containing 10% of FBS were stimulated by the T-cell mitogen concanavalin A (5 mg/l, ConA, Sigma) for 120 h at 37°C. Proliferation was measured using the pyrimidine analog 5-bromo-deoxyuridine, which was quantified in PBMC by a cellular enzyme immunoassay as described earlier (Watzl et al, 2000).
Quantification of cytokine secretion
PBMC at 1 × 109 cells /l were cultured in medium containing 10% of FBS and stimulated by 5 mg/l ConA for 24 h at 37°C (interleukin-2, -4 IL-2, IL-4) or by 1 μg/l LPS (TNFα, transforming growth factor-β, TGFβ). Cell-free supernatants were collected and stored at −80°C until analysis. TNFα, IL-2, and IL-4 were measured by sandwich-ELISAs as described earlier (Watzl et al, 2000). For TGFβ, a sandwich-ELISA was developed using an anti-human TGFβ monoclonal antibody (2 mg/l PBS, pH 7.4; R&D, Wiesbaden, Germany) as capture antibody and a monoclonal biotin-labeled mouse anti-human TGFβ antibody (300 μg/l reagent diluent, R&D) as detection antibody. TGFβ in supernatants had to be activated by mixing 0.5 ml of supernatants with 0.1 ml 1 M HCl. After incubation for 10 min, 0.1 ml of 1.2 M NaOH/0.5 M HEPES was added, then the mixture was pipetted on a microtiter plate. Optical density was measured with a multiplate spectrophotometer (Molecular Devices) at 405 nm with data expressed as nanogram per liter compared to the optical density of recombinant TGFβ.
Quantification of TNFα mRNA
PBMCs were LPS-stimulated under conditions as already described for the ELISA-based TNFα analysis, except that duration of LPS-incubation for mRNA detection was 4 h. Total RNA was extracted from the cells using the guanidine isocyanate/acid phenol method described by Chomczynski and Sacchi (1987). The quantity and quality of the RNA were measured at 260/280 nm in a spectrophotometer (Lamda Bio 20 UV/VIS, Perkin-Elmer, Wellesley, MA, USA).
Reverse transcription (RT) and polymerase chain reaction (PCR) were performed using the Ready-to-Go RT–PCR kit (Amersham Pharmacia Biotech; Freiburg, Germany). The respective sequences used for generation of sense and antisense primers were nt 350–373 and nt 795–772 of TNFα cDNA (Acc. XM_165823.1) and nt 71–94 and nt 570–574 of GAPDH cDNA (Acc. BC004109) used as internal standard for normalization. All primers were tested for linearity over cycle number, and analyses were all carried out in the linear portion of the curve, therefore allowing semiquantitative analysis of mRNA amount. PCR products were run on 1.5% agarose gel in TBE buffer (89 mM Tris, 89 mM boric acid, 2 mM EDTA, pH 7.9) and ethidium bromide stained bands were visualized and quantified using computer-based image analysis (FluorS Imager; Biorad, München, Germany). Quantities of each PCR product were normalized by dividing the average gray level of the signal by that of the corresponding GAPDH PCR product. Data are expressed as arbitrary units (AU).
Lytic activity of NK cells
Lytic activity of NK cells against K562 target cells (effector:target ratios 50:1, 25:1, 12.5:1) was measured with a recently described flow cytometric method (Watzl et al, 2000).
Assessment of phagocytic activity (percentage of phagocytic-active cells) was based on a recently described flow cytometric method (O'Gorman, 2002).
Apoptosis was measured in PBMC using Annexin V with a recently described flow cytometric method (Roser et al, 2001).
Subjects were randomly assigned to a different treatment order regarding the four beverages. As a consequence, only three subjects consumed all beverages in the same sequence during the four phases of beverage consumption. To test whether baseline data for one beverage were significantly different in the four different phases, data were analyzed by factorial ANOVA with ‘time’ as dependent variable and ‘beverage’ and ‘phase’ as factors. When no significant differences between baseline data of the four phases for one beverage were observed, data of the four phases were combined to one experimental period resulting in a total number of 24 subjects with blood collections at weeks 0, 1, and 2. Repeated-measures ANOVA were used with ‘time’ as within-subject factor and ‘beverage’ as between-subject factor to analyze treatment effects. Results are reported as means±standard error of the mean (s.e.m.). All statistical calculations were performed with the StatView program (SAS Institute 1998, Cary, NC, USA).
Mean age of the study subjects was 30.6±1.4 y. Body mass index (kg/m2) and body mass (kg) were 23.5±0.4 and 79.7±1.4, respectively. All participants tolerated the intervention with the four beverages well and completed the study. Maximum blood ethanol concentrations in subjects consuming red wine were 15.9 and 15.0 mM in subjects consuming the 12% ETOH dilution (Watzl et al, 2002).
No beverage-specific differences at baseline for the four different phases were observed. Therefore, data of the four phases for one beverage were combined into one phase of beverage consumption. The capacity of mitogen-activated PBMC to produce TH1-(IL-2) and TH2-(IL-4) lymphocyte-specific cytokines as well as monocyte-specific cytokines (TGFβ, TNFα) did not change significantly over time when the four different beverages were compared (Table 1). In order to study the effect of ETOH on cytokine gene expression, we measured TNFα mRNA expression. No beverage-specific effects on TNFα mRNA were observed (Table 1). Phagocytic activity of granulocytes and monocytes ex vivo was not different at baseline and was not significantly affected by the consumption of the different beverages (Table 2). Apoptosis of T lymphocytes, T-lymphocyte responsiveness to mitogen-activation and lytic activity of NK cells (data are only shown for the effector:target ratio of 25:1) were also not modulated by the 2 weeks of beverage consumption (Table 2).
We have recently shown that the acute intake of moderate amounts of red wine or 12% ETOH has no effect on the immune system of healthy men in the following 24 h (Watzl et al, 2002). The objective of the present study was to investigate the immunomodulatory effects of a daily moderate intake of RW, DRW, RGJ and of 12% ETOH over a period of 2 weeks. In order to study whether neutrophils, monocytes, and lymphocytes were specifically affected by the different beverages, cell-specific functional assays were applied. Neutrophil functions such as chemotaxis and production of reactive oxygen species have previously shown to be affected by ethanol and polyphenols (Patel et al, 1996; Lu et al, 2001). Acute ETOH exposure in humans (five glasses of wine or more) induced neutrophil apoptosis (Singhal et al, 1999a), which is expected to impair neutrophil functions. In the present study, however, no significant effects on neutrophil as well as monocyte phagocytosis were observed with the different beverages suggesting that neither ETOH nor red grape-associated polyphenols were effective. In vitro, ETOH exposure has been shown to attenuate dose-dependently the phagocytic activity of human monocytes via the Fc-receptor (Morland & Morland, 1984). While ETOH concentrations (12 or 22 mM) comparable to those measured in the blood of our study subjects (15.9 mM; Watzl et al, 2002) also had no effect in vitro confirming our in vivo observations, higher in vitro ETOH concentrations significantly suppressed phagocytic activity (Morland & Morland, 1984).
The production of TNFα by LPS-activated monocytes as well as TNFα mRNA expression were not significantly affected by the treatment. In another study with acute alcohol exposure (a single intake of 80 g ethanol with wine or beer), no changes in plasma concentrations of monocyte-derived cytokines such as TNFα and IL-1α/-β were measured (Mohadjer et al, 1995). In vitro, only high, but still physiological doses (≥25 mM) as well as pharmacological doses of ETOH (>40 mM) significantly decreased TNFα production by human monocytes (Verma et al, 1993; Szabo et al, 1996; Arbabi et al, 1999). In addition, a concentration of 25 mM ETOH in vitro also reduced TNFα mRNA levels (Szabo et al, 1996). Blood ETOH concentrations in subjects of the present study may not have been high enough to affect LPS-induced TNFα production at the protein and at the mRNA level.
ETOH or polyphenol intake did not modulate lymphocyte-derived cytokine production (IL-2, IL-4). For IL-4, a TH2-lymphocyte-specific cytokine, no differences in serum levels between controls and alcoholic patients were observed in another study (Laso et al, 1998) supporting our observations that daily ETOH consumption at this level has no effect on TH2-lymphocytes. However, binge drinking of up to 3.1 l of beer significantly reduced IL-2 production, a TH1-specific cytokine (Bagasra et al, 1989). In an animal study, a long-term intake of high ETOH doses significantly increased IL-2 production independent of the dietary composition (Watzl et al, 1993). This suggests that in contrast to TH2-lymphocytes ethanol modulates TH1-lymphocytes depending on dose and length of intake period. Lymphocyte proliferative responsiveness to mitogen-activation was also not influenced by the different beverages. This is in agreement with an earlier human study, which did not observe acute effects of ethanol after alcohol consumption (Mohadjer et al, 1995).
In the present study, lytic activity of NK cells was not affected by ETOH or by RW. Another study with acute ETOH consumption (blood ETOH levels 8.7 and 19.3 mM) also did not observe a change in NK cell lytic activity (Ochshorn-Adelson et al, 1994). In contrast, chronic alcoholics without liver disease were shown to have a significantly increased number of NK cells and a parallel increase in NK cell lytic activity (Laso et al, 1997). Several studies have investigated the effect of wine flavonoids on NK cell function. While quercetin in vitro (1 mM) significantly decreased lytic activity of NK cells (no effects at lower concentrations) (Exon et al, 1998), in animal models, quercetin (100 mg/kg) and catechin (125–500 mg/kg) increased lytic activity of NK cells (Ikeda et al, 1984; Exon et al, 1998). The doses used in in vitro studies and those obtained in the animal studies were much higher than the plasma flavonoid concentrations in our study subjects after a single intake of these beverages. The major polyphenol in the beverages RW, DRW, and RGJ was the anthocyanin malvidin-3-glucoside, which contributed 80% of the total anthocyanins in RW and DRW and 69% in RGJ (Bub et al, 2001). The maximum malvidin-3-glucoside plasma concentrations were 1–3 nM, which were reached within 120 min following beverage consumption (Bub et al, 2001). This indicates that the major polyphenol from red wine was absorbed, but only low quantities were available. Whether these plasma concentrations are significant to induce physiological activity can only be speculated at present.
Results from recent studies reported that acute alcohol intake (five glasses of wine) enhanced the percentage of apoptotic neutrophils and monocytes (Singhal et al, 1999a,1999b). So far, no information was available on the percentage of lymphocyte apoptosis after moderate ETOH or polyphenol intake. The present data show that neither RW nor 12% ETOH at a volume of 500 ml/day affected lymphocyte apoptosis. TGF-β production by LPS-activated monocytes, which has been demonstrated to partly mediate the increase in monocyte apoptosis by ETOH (Singhal et al, 1999b), also did not differ between the beverages.
In conclusion, the results of the present study clearly show that the daily intake of different alcoholic beverages at a volume of 500 ml over a period of 2 weeks had no significant immunomodulatory effects. In addition, a high polyphenol intake with RGJ and DRW did not result in immunosuppression as suggested by results from several in vitro studies (Middleton et al, 2000). These data indicate that daily RW consumption at a level, which inversely correlates with CVD risk, has no adverse effects on the immune system. Whether longer time periods with such alcohol consumption patterns result in more significant changes of immune functions cannot be answered by the present study.
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We gratefully acknowledge the competent technical assistance of the IEP technicians and are indebted to all study participants for contributing continuously to this study.
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Watzl, B., Bub, A., Pretzer, G. et al. Daily moderate amounts of red wine or alcohol have no effect on the immune system of healthy men. Eur J Clin Nutr 58, 40–45 (2004). https://doi.org/10.1038/sj.ejcn.1601742
- red wine
- red grape juice
- immune system
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