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Article

Prolonged Tomato Juice Consumption Has No Effect on Cell-Mediated Immunity of Well-Nourished Elderly Men and Women¹

Institute of Nutritional Physiology, Federal Research Centre for Nutrition, Karlsruhe, Germany and ^* Institute of Nutritional Sciences, Justus-Liebig-University, Giessen, Germany

²To whom correspondence should be addressed.

	ABSTRACT

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The immunomodulatory potential of carotenoids has been investigated thoroughly only for ß-carotene. Data on the immunomodulatory activity of other carotenoids such as lycopene are scarce. The objective of this study was to investigate the effects of prolonged tomato juice consumption on cell-mediated immunity of well-nourished healthy elderly persons. In an intervention study, 33 female and 20 male subjects (aged 63–86 y) consumed 330 mL/d tomato juice (47.1 mg/d lycopene) or mineral water for 8 wk. Immune status was assessed by measuring number and lytic activity of natural killer (NK) cells, secretion of cytokines [interleukin (IL)-2, IL-4, tumor necrosis factor- (TNF-)] by activated peripheral blood mononuclear cells (PBMC), lymphocyte proliferation, and delayed-type hypersensitivity (DTH) skin responses. Tomato juice consumption resulted in significantly increased plasma lycopene and ß-carotene concentrations over time. In both treatment groups, TNF- and IL-4 secretion were increased at the end of the intervention period, whereas IL-2 secretion was decreased. Tomato juice consumption had no effect on lymphocyte proliferation, DTH or the number of NK cells. Lytic activity of NK cells was increased in both groups at the end of the intervention period. In conclusion, these results show that prolonged tomato juice consumption increased plasma lycopene concentrations without significantly affecting cell-mediated immunity in well-nourished elderly subjects.

KEY WORDS: • tomato juice • lycopene • elderly humans • cell-mediated immunity

	INTRODUCTION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
A high consumption of tomato and tomato-based products is associated consistently with a low risk of cancer for a variety of anatomic sites (Giovannucci 1999 ). Numerous potentially beneficial compounds are present in tomatoes, with lycopene as the major phytochemical (Beecher 1998 ). Although the active compounds in tomatoes contributing to the observed reduction of cancer risks are presently unknown, the benefits of tomatoes are often attributed to lycopene (Clinton 1998 ), and results from a recent study support this assumption (Gann et al. 1999 ). Few studies to date have looked at the immunomodulatory activity of lycopene, which may contribute to the observed cancer risk reduction with high consumption of tomato products. In vitro, lycopene suppressed T-helper 2 (TH2)³ cell clone–mediated antibody production in unprimed spleen cells. It had no effect on interleukin (IL)-5 production of TH2 cells (Iyonouchi et al. 1996 ). In a mouse model, during tumorigenesis, lycopene normalized the change of intrathymic T-cell differentiation by increasing the CD4+ cells (Kobayashi et al. 1996 ). In a human intervention trial, supplementation with 15 mg/d lycopene for 28 d induced no changes in monocyte surface marker expression of healthy adults (Hughes et al. 1997 ).

We have recently shown that in healthy adults a low carotenoid diet resulted in significantly reduced proliferation of peripheral blood mononuclear cells (PBMC). In addition, secretion of IL-2 and IL-4 by these cells was also significantly decreased. After 2 wk of supplementation with 330 mL/d tomato juice, lymphocyte functions were normalized (Watzl et al. 1999 ), whereas plasma lycopene concentrations were significantly higher compared with baseline (Müller et al. 1999 ). DNA from PBMC of these subjects had significantly lower endogenous levels of strand breaks, indicating that tomato juice consumption induced protective mechanisms in PBMC (Pool-Zobel et al. 1997 ). These results have been confirmed by a recent study, which reported increased resistance of lymphocyte DNA to oxidative damage after tomato consumption (Riso et al. 1999 ). Whether enhanced antioxidative protection of PBMC after tomato consumption is related to an immunomodulatory activity of tomato compounds such as lycopene is currently not known.

The results of our first study prompted us to conduct an intervention trial with healthy, noninstitutionalized elderly people instead of young subjects to investigate the effect of prolonged tomato juice consumption on cell-mediated immunity. Elderly subjects have a dysregulation of immune responses, mainly as a result of changes in cell-mediated immunity (Lesourd 1997 ). Therefore, any immunostimulatory activity of tomato or tomato-specific phytochemicals such as lycopene should be seen more clearly in subjects with age-related impaired immune functions.

	SUBJECTS AND METHODS

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Subjects.

Subjects were participants of the Longitudinal Study in an Aging Population of Giessen (GISELA), Germany, in which the nutritional and health status of free-living elderly people is investigated at yearly intervals. Of the 453 subjects included in the survey, selection for the participants of the tomato study was based on the following exclusion criteria: smoking, alcohol consumption > 50 g/d, food allergies, cancer, coronary heart disease, chronic inflammatory diseases (rheumatoid arthritis, Crohn’s disease, colitis ulcerosa), diabetes, asthma, use of prescription medication or nonsteroidal anti-inflammatory drugs on a regular basis, use of vitamin or mineral supplements for the last 3 mo, corticosteroid treatment and intake of immunostimulators for the last 4 wk. Fifty-three elderly subjects were enrolled after screening. The study was approved by the Ethical Committee of the Department of Medicine, Justus-Liebig-University Giessen and all participants gave their consent in writing.

Study design.

This study was conducted during the months of May–July, 1998. Subjects were assigned randomly to the control or intervention group. Energy and nutrient intakes of the study subjects before the study period were assessed by means of a validated 3-d estimated food record (Lührmann et al. 1999 ). Subjects of the tomato juice group consumed daily 330 mL tomato juice (47.1 mg lycopene, 1.7 mg ß-carotene; Schoenenberger, Magstadt, Germany) for 8 wk. Subjects of the control group consumed the same volume of mineral water. Subjects were instructed to drink tomato juice or water with their main meal. Because the current intake of lycopene in Germany is ~1 mg/d (Pelz et al. 1998 ) and the tomato juice provided ~40 times more lycopene, subjects were allowed to continue with their regular diet throughout the study period including tomato products in the control group. During the entire intervention period, subjects were asked to protocol any diseases or medicine use. Blood samples from fasting subjects were collected between 0700 and 1030 h.

Measurement of carotenoids and ascorbic acid.

Carotenoids in tomato juice, fetal bovine serum (FBS) and plasma were measured by reversed-phase HPLC as described earlier (Müller et al. 1999 ). Plasma ascorbic acid concentrations were determined by a modified 2,4-dinitrophenylhydrazine method (Lowry et al. 1943 ).

Isolation of PBMC and preparation of serum.

Blood was drawn into K⁺-EDTA tubes (proliferation and cytokine secretion) and lithium heparin tubes [natural killer (NK) cell lytic activity]. PBMC were isolated by density gradient centrifugation using Histopaque 1077 (Sigma, Deisenhofen, Germany) and resuspended in complete RPMI-1640 culture medium (Life Sciences, Eggenstein-Leopoldshafen, Germany), containing 5% (v/v) heat-inactivated FBS (Life Sciences), L-glutamine (2 mmol/L), penicillin (100,000 U/L) and streptomycin (100 mg/L). Serum from each subject was heat inactivated for 30 min at 56°C.

Lymphocyte proliferation.

PBMC at 1 x 10⁹ cells/L in medium containing 5% of either FBS or autologous serum 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 thymidine analog 5-bromo-deoxyuridine, which was quantitated in PBMC by a cellular enzyme immunoassay as described earlier (Watzl et al. 1999 ).

Quantification of cytokine secretion.

PBMC at 1 x 10⁹ cells/L were cultured in medium containing 5% of either FBS or autologous serum and stimulated by 5 mg/L ConA for 48 h at 37°C (IL-2, IL-4) or by 10 mg/L lipopolysaccharide (Difco, Augsburg, Germany) for 24 h at 37°C (TNF-). Cell-free supernatants were collected and stored at -80°C until analysis. IL-2 and IL-4 were measured by sandwich-ELISA as described earlier (Watzl et al. 1999 ). For TNF-, a sandwich-ELISA was developed using an anti-human TNF- monoclonal antibody (25 mg/L PBS, pH 7.4; Endogen, Eching, Germany) as capture antibody and a monoclonal biotin-labeled mouse anti-human TNF- antibody [375 µg/L PBS-Tween and 4% v/v bovine serum albumin (BSA); Endogen] as detection antibody.

Percentage and lytic activity of NK cells.

The percentage of NK cells was determined by flow cytometry (FACSCalibur, Becton Dickinson, Heidelberg, Germany). PBMC were incubated with a phycoerythrin-conjugated monoclonal antibody NCAM16.2/anti-CD56 (Becton Dickinson) and a FITC-conjugated monoclonal antibody anti-CD3 (Becton Dickinson), washed and fixed with 1% paraformaldehyde (Sigma). 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 (Chang et al. 1993 ) and calculated as the percentage of dead target cells in the test samples minus the percentage of dead target cells in the control samples without effector cells.

Assessment of delayed-type hypersensitivity (DTH).

DTH skin response was assessed with Multitest-CMI (GN Pharma, Fellbach, Germany) loaded with glycerine control and seven common antigens. The device was administered on the forearm by a person who was blinded to the study treatment assignment. The diameter of positive reactions was measured 48 h after administration of the test. According to the manufacturer‘s instruction, an induration of 2 mm was considered positive.

Statistical analyses.

Normal distribution of the data was analyzed by using the Kolmogorov-Smirnov normality test. Baseline data vs. post-treatment data within groups were analyzed by using Student’s paired t test or Wilcoxon’s rank test for data that are not normally distributed. Differences between treatment groups were analyzed by using Student’s t test for independent samples (or the Mann-Whitney U test for data that were not normally distributed) on mean pre- to postintervention differences. To assess the plasma lycopene-NK lytic activity relationship, Spearman correlation coefficients were computed. Statistical significance was accepted at the P < 0.05 level. All statistical calculations were performed with the StatView program (SAS Institute, Cary, NC).

	RESULTS

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Three subjects were excluded from the study because they had to receive a drug treatment during the intervention period; 50 subjects completed the study with 21 (13 women, 8 men) subjects in the control and 29 (19 women, 10 men) in the tomato juice group. No other subjects reported any intercurrent diseases during the study. On the basis of the results of the 3-d estimated food record, there were no differences between groups at the beginning of the study in the intake of energy, protein, carbohydrates and fat as well as in vitamin E and zinc (data not shown). The ß-carotene and ascorbic acid intakes before the study period also did not differ between groups (control 4.57 ± 2.59 mg/d and 116.5 ± 49.9 mg/d, tomato juice group 4.24 ± 2.53 mg/d and 119.1 ± 61.5 mg/d). Plasma ascorbic acid concentrations were measured only at the end of the study period and did not differ between groups (control 72.7 ± 18.2 µmol/L, tomato juice group 72.7 ± 14.2 µmol/L). No differences were observed between groups in average age (control 70.5 ± 5.2 y, tomato juice 69.7 ± 5.8 y) and body mass index (control 26.7 ± 3.0 kg/m², tomato juice 26.6 ± 2.4 kg/m²). All subjects maintained body weight throughout the study (data not shown).

There was no significant difference in plasma carotenoid concentrations between groups at baseline (Table 1 ). Tomato juice consumption significantly increased plasma concentrations of all-trans- and cis-lycopene (threefold), -cryptoxanthin and ß-carotene. (Table 1) . No carotenoids or tocopherols were detected in FBS.

Flow cytometry revealed no significant differences in the percentages of NK cells between groups at baseline and after the dietary intervention (Table 3 ). The lytic activity at baseline did not differ between the groups, whereas during the intervention period, lytic activity increased significantly in both groups. A significant correlation between plasma all-trans-lycopene concentrations and lytic activity of NK cells (r = 0.367, P = 0.049) was seen in the tomato juice group. Because we observed an increase in both groups at all effector:target ratios, only the results for the 25:1 ratio are shown in Table 3 .

	DISCUSSION

TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The immunomodulatory potential of carotenoids has been investigated thoroughly only for ß-carotene. Data on the immunomodulatory activity of other carotenoids such as lycopene are scarce. We showed recently that 2 wk of tomato juice consumption (supplying 40 mg/d lycopene) after a 2-wk period of a low carotenoid diet stimulated lymphocyte proliferation and IL-2 secretion of PBMC in healthy adults (Watzl et al. 1999 ). The objective of this study was to investigate the effects of prolonged tomato juice consumption on cell-mediated immunity of well-nourished healthy subjects with a higher risk for impaired immune functions such as elderly people.

Tomato juice consumption significantly increased plasma lycopene and ß-carotene concentrations. In relation to the average plasma ß-carotene and ascorbic acid concentrations of elderly subjects (age > 65 y) in Germany (Heseker et al. 1992 ) and other countries (Pallast et al. 1999 , Vogel et al. 1997 ), our study subjects showed higher plasma ß-carotene and ascorbic acid concentrations. This suggests that the participants in our study have been well-nourished, which is of relevance for the interpretation of the immunological results.

In our study, we sought to determine whether tomato juice consumption affects cytokine secretion capacity of PBMC from elderly subjects. The majority of studies in elderly subjects show that lymphocytes produce significantly less TH1 subset–derived cytokines such as IL-2 and more TH2 cytokines such as IL-4, indicating a dysregulation between TH1 and TH2 subsets (Rink et al. 1998 ). The production of proinflammatory cytokines such as TNF- seems to be enhanced in elderly people compared with young adults (Rink et al. 1998 ). During our intervention, the secretion capacity of PBMC for TNF- and IL-4 was increased in both groups, whereas subjects in both groups showed reduced IL-2 production after 8 wk of tomato juice consumption. These results clearly indicate that tomato juice consumption (i.e., a high intake of lycopene) does not interfere with the regulation of cytokine secretion capacity in elderly subjects. This conclusion is supported by our findings that PBMC cultured in medium containing 5% FBS (free of carotenoids and tocopherols) or 5% autologous serum (high concentrations of tomato-derived lycopene) yielded similar results. The reason for the significant changes in cytokine secretion observed in both groups is unknown.

Reduced lymphocyte proliferation is a common phenomenon observed in elderly subjects (Lesourd 1997 ), and enhancement of this T-cell function by dietary means would be an interesting approach to stimulate immune functions in this vulnerable population. In our study, proliferation of activated PBMC cultured with medium containing 5% FBS or autologous serum was not affected by the dietary intervention and did not differ between groups. This suggests that tomato juice–derived compounds in PBMC or in autologous serum do not influence lymphocyte proliferation in vitro. However, the addition of tomato juice to a low carotenoid diet stimulated lymphocyte proliferation in adults (Watzl et al. 1999 ). No other studies have looked at the effect of tomato juice and/or lycopene on lymphocyte proliferation.

Alterations of the immune system during aging include functions of NK cells (Solana et al. 1999 ). The results of our study show that the percentage of NK cells in PBMC was not affected by the dietary intervention. In addition, lytic activity of NK cells was increased independently of the dietary treatment. However, a weak significant positive correlation between plasma all-trans-lycopene concentrations and lytic activity of NK cells was seen in the tomato juice group. This suggests that high plasma all-trans-lycopene concentrations may stimulate NK cell activity. Because we did not observe differences between treatment groups and multiple factors modulate this activity, we cannot speculate at this time about potential mechanisms of lycopene.

The age-related impaired cell-mediated immunity is reflected in the inability of elderly people to mount a DTH (Bogden and Louria 1997 ), and a low DTH response has been shown to be associated with increased mortality in healthy elderly people (Wayne et al. 1990 ). In both groups of our study, the range for the antigen score and cumulative score was comparable to those observed in other studies of healthy elderly subjects (Girodon et al. 1999 , Pallast et al. 1999 , Santos et al. 1997 ), suggesting a normal DTH response in our elderly subjects. DTH was not significantly affected by the dietary intervention in our subjects. There are no other studies in the literature investigating the effect of carotenoid-rich vegetables or lycopene on DTH.

Studies have shown that tomato juice consumption reduces oxidative DNA damage in PBMC (Rao and Agarwal 1998 , Riso et al. 1999 ). Prevention of such oxidative damage is one potential mechanism for an immunomodulatory effect of carotenoids (Meydani et al. 1995 ). Although we found a weak positive correlation between plasma all-trans-lycopene and NK cell activity, no effect of tomato juice consumption on cell-mediated immunity was observed.

In conclusion, our study suggests that in well-nourished elderly people, supplementation with tomato juice resulting in high plasma lycopene levels does not modulate cell-mediated immunity. It is likely that the good nutritional status of our elderly subjects led to their normal immune functions. This hypothesis is supported by the results of our study with young healthy adults consuming a low carotenoid diet. Supplementation with tomato juice significantly stimulated various T-lymphocyte functions in these subjects (Watzl et al. 1999 ).

	ACKNOWLEDGMENTS

 
The authors thank M. Broßart, T. Gadau, M. Giorgi-Kotterba, C. Kunz, G. Schultheiss and U. Stadler-Prayle for their excellent technical assistance and the elderly subjects for taking part in this study. The guidance of K. Briviba in the carotenoid analysis is highly appreciated. Tomato juice was provided by Schoenenberger Pflanzensäfte GmbH, Magstadt, Germany, which is gratefully acknowledged.

	FOOTNOTES

 
¹ Presented in poster form at Experimental Biology 99, April 20, 1999, Washington, DC [Watzl, B., Bub, A., Blockhaus, M., Müller, H., Herbert, B., Lührmann, P., Neuhäuser-Berthold, M. & Rechkemmer, G. (1999) Prolonged tomato juice consumption has no effect on immune function and on plasma antioxidant activity of well-nourished elderly. FASEB J. 13: A590 (abs.)].

³ Abbreviations used: ConA, concanavalin A; DTH, delayed-type hypersensitivity; FBS, fetal bovine serum; IL, interleukin; NK, natural killer; PBMC, peripheral blood mononuclear cells; TH, T helper; TNF-, tumor necrosis factor-.

Manuscript received January 4, 2000. Initial review completed February 11, 2000. Revision accepted March 9, 2000.

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