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-Tocopherol and Selenium Facilitate Recovery from Lipopolysaccharide-Induced Sickness in Aged Mice1,2
,4
* Division of Nutritional Sciences and
Department of Animal Sciences, University of Illinois, Urbana, IL 61801
4To whom correspondence should be addressed. E-mail: rwjohn{at}uiuc.edu.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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-tocopherol (-T) and selenium inhibit LPS-induced sickness behavior in aged mice. Male BALB/c mice were fed modified AIN93-M diets that were low, adequate, or high in both -T (10, 75, or 500 mg/kg) and selenium (0.05, 0.15, or 2 mg/kg) from 18 to 21 mo of age. Sickness was quantified by measuring time in social exploration of a novel juvenile conspecific. The lipopolysaccharide treatment reduced social exploration by 74% at 2 h, regardless of diet. By 4 h, aged mice fed the low diet were 88% less social, whereas mice fed the adequate and high diets displayed only 
40% reductions due to LPS treatment. Mice fed the low diet had greater LPS-induced weight loss than mice fed the high diet. Plasma -T concentration and glutathione peroxidase (GPX) activity increased with each increment in -T and selenium 24 h post-LPS treatment. Brain -T concentration and GPX activity were lower in mice fed the low diet than in those fed the adequate or high diet. Regardless of diet, interleukin (IL)-6, IL-1ß, and tumor necrosis factor (TNF) mRNA levels were elevated by LPS 3-fold in cortex, cerebellum, striatum, and hippocampus. Thus, antioxidants inhibit sickness behavior independently of IL-6, IL-1ß, and TNF mRNA levels 2 h post-LPS in the brain regions analyzed. Taken together, these findings suggest that adequate intake of dietary -T and selenium may help promote recovery from gram-negative bacterial infection in the aged.
KEY WORDS: • aging • cytokines • sickness behavior • vitamin E • selenium
The elderly represent the fastest growing segment of the U.S. population. The census bureau projects that by the year 2050, Americans over 65 y old will represent almost 21% of the total population, 82 million people. Furthermore, those older than 85 y are projected to increase in number from 5 million today, to 31 million by the year 2050. These projections are of concern because debilitating chronic conditions such as cancer, infections, and neurodegenerative diseases are inextricably linked to advancing age and will undoubtedly strain the financial, medical, and family resources needed to support and care for the elderly.
Aging results in impaired function of the immune system. The specific immune responses that are altered with advancing age are diverse and have been examined in several publications (1–3). In brief, the elderly exhibit poor antibody response to vaccination, reduced numbers of T cells (CD4+ helper and naïve T lymphocytes), decreased proliferative response to mitogens and antigens, phagocyte and cytokine dysregulation, and changes in the complement system. Furthermore, aging is also associated with increased incidence of nutritional deficiencies in energy, protein, vitamins, and trace elements, especially in the elderly who are hospitalized or institutionalized (1,4). All of these changes are thought to contribute to the heightened susceptibility to, impaired recovery from, and increased mortality associated with infections (1). To various degrees, intervention studies in the elderly have shown that correction of age-related nutrient deficiencies improves or restores some indicators of immune function (5–7). However, due to the limitations of human intervention trials, and the inherent variability within them, no definitive conclusions can be drawn regarding a direct link between certain nutrients and improvement of clinical end-points such as duration of sickness or infection-related mortality.
Lipopolysaccharide isolated from Escherichia coli bacteria is recognized by immune cells as a pathogen-associated molecular pattern (PAMP)5 and activates innate immune responses. Inflammatory cytokines such as interleukin (IL)-1ß, IL-6 and tumor necrosis factor (TNF) are key regulators of innate immunity and are also directly responsible for the characteristic set of sickness behaviors that accompany infections (8,9). Peripheral infection or administration of LPS results in de novo activation of brain microglia cells. Activated microglia produce, among other molecules, inflammatory cytokines, which are primarily responsible for induction and maintenance of sickness behaviors (10). The administration of LPS, therefore, provides a model with which to study immune system activation with concomitant displays of quantifiable sickness behaviors.
Reactive oxygen species (ROS) and peroxides, once regarded only as toxic by-products of metabolism, are now proposed to function as highly controlled mediators of cell signaling as well as regulators of gene transcription. Such functions are being found in cells involved with immune (11), pancreatic (12), cardiovascular (13), neurological (14), and hepatic (15) systems. For example, recent studies confirm that ROS and peroxides play a role in neutrophil (16), macrophage (17), dendrite (11), and microglia (18) intracellular signaling pathways that promote an inflammatory state. Several mechanisms are currently purported to explain how oxidative stress influences inflammatory cytokine production. Over a decade ago, the factor responsible for activating the transcription of multiple inflammatory genes, nuclear factor (NF)
B, was found to be activated by hydrogen peroxide (19). Recently, NADPH oxidase 4 isozyme production of ROS was found to be critical for LPS activation of NFB (20). Together, these studies establish that specific cellular events required to produce inflammatory mediators are regulated in part by ROS and peroxides. Therefore, age-associated dysregulation of immune function and inflammatory cytokines may be caused by an age-dependent increase in the ROS and peroxide burden.
We demonstrated that -tocopherol (-T), a potent lipid-soluble antioxidant, inhibits LPS-induced lipid peroxidation and inflammatory cytokine production in primary murine microglia (21). Furthermore, 3 d of i.p. -T pretreatment in mice decreased both LPS-induced lipid peroxidation and whole-brain IL-6 protein compared with mice administered vehicle pretreatment (21). In addition, we demonstrated that injected and dietary -T and selenium enhance recovery from LPS-induced sickness in adult mice (22). In this study, we investigated the potentially important effects of different dietary -T and selenium levels on LPS-induced immune system activation in aged mice.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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-T and selenium were purchased from Dyets. The nutrient composition and references (23) for vitamin and mineral premixes for the diets are presented in Table 1. Independent analysis determined that the low, control, and high diets contained 6.6, 68, and 623 mg/kg -T and 0.05, 0.11, and 1.7 mg/kg selenium, respectively (Woodson-Tenent Laboratories).
Experimental procedures.
An initial study was conducted to determine the effects of dietary -T and selenium on LPS-induced sickness behavior in aged mice. Mice were allotted to dietary treatments on the basis of body weight and gradually introduced to the experimental diets (Table 1) over a 1-wk period. Mice consumed the experimental diet ad libitum for a 12-wk period during which food intake and body weight were monitored. The duration and levels of dietary supplementation were based on several reports (24–26) in which successful tissue distributions and treatment effects were described. Mice were provided fresh food 3 times/wk and new bowls once a week. At the end of the 12-wk period, mice were subjected to the social exploration test to establish a baseline level of activity. Immediately after the test, mice were injected i.p. with vehicle or vehicle containing 1 µg LPS. Thus, the treatments comprised a 3 x 2 factorial arrangement of diet (low, adequate, or high levels of -T and selenium) and LPS (0 or 1 µg), n = 6. At 2, 4, 8, and 24 h after injection of LPS, mice were subjected to the social exploration test using a novel juvenile mouse each time. After the 24-h recording, mice were anesthetized by CO2 inhalation and killed by exsanguination via cardiac puncture. Blood samples were collected into EDTA-coated tubes and the resultant plasma was stored at –80°C and later assayed for -T and cytokine concentrations and GPX activity. Transcardial perfusion was then performed using sterile filtered PBS containing 2 mmol/L EDTA to flush residual blood out of tissue vasculature. Brain samples were obtained, snap frozen in liquid nitrogen, and stored at –80°C for later determination of -T and cytokine concentrations and GPX activity.
A follow-up experiment was performed that was identical to the above except tissues were collected 2 h post-LPS treatment for determination of cytokine protein and mRNA levels. This time point was chosen based on previous studies from our laboratory establishing that the peak of LPS-induced sickness occurred 2 h post-LPS administration. To facilitate preservation of cortex, cerebellum, hippocampus, and striatum mRNA, brain regions were immediately placed in RNAlater solution (Ambion) and stored at –20°C. Real-time quantitative PCR was performed within 1 mo.
HPLC analysis.
Analysis of -T concentrations in brain and plasma samples was conducted using a Shimadzu VP series HPLC system equipped with a degasser, solvent mixer, manual injector, and fluorescence detector. All solvents were HPLC grade, and mobile phase solvents were filtered through a 22-µm nylon membrane before use. The external standard, -T, was purchased from Sigma Chemical. The internal standard tocol was purchased from Matreya. The mobile phase consisted of methanol:water (98:2) and was passed at a flow rate of 1 mL/min through a Supelco Discovery C18 reverse-phase column for fluorescent excitation (295 nm) and emission (320 nm) detection. Extraction of -T from brain and plasma was performed as previously described (21,22). All procedures were conducted under gold fluorescent light conditions to protect -T from degradation.
GPX activity. Glutathione peroxidase activity was quantified in brain and plasma samples using a kinetic colorimetric assay from Cayman Chemical. In brief, frozen brain samples (–80°C) were thawed and immediately homogenized in 1 mL of homogenizing buffer (50 mmol/L Tris-HCl, pH 7.5, 5 mmol/L EDTA, 1 mmol/L dithiothreitol) using a Dounce homogenizer with 10 strokes of pestle A and 10 strokes of pestle B (Kontes Glass). Tissue homogenates were centrifuged at 10,000 x g for 10 min at 4°C. Supernatants were immediately diluted in PBS and assayed for GPX activity. Frozen plasma samples (–80°C) were thawed and diluted in PBS before analysis. Samples were monitored 1 time/min for 7 min for a decrease in absorbance at 340 nm using a Molecular Devices OPTImax® tunable microplate reader.
Social exploration.
Depression in time engaged in social exploration of a novel juvenile conspecific is a sensitive index of sickness behavior (9). Therefore, this model was used to probe the potential of -T and selenium to block or attenuate LPS-induced sickness in aged mice according to a previously published methodology (22). In brief, a juvenile conspecific was placed in the home cage of an experimental mouse for a 10-min test. The social interaction between them was video-recorded and the duration engaged in social exploration was determined from the video records by a trained observer who was unaware of the experimental treatments. Social exploration was determined as the amount of time that the experimental mouse spent investigating (e.g., anogenital sniffing, trailing) the juvenile mouse (27).
Plasma interleukin-6. IL-6 protein levels were determined using an in-house sandwich ELISA. A detailed description of the procedure was published previously (21). The assay was sensitive to 7.8 ng/L IL-6, and the inter- and intra-assay CV were < 10%.
Real-time quantitative PCR.
Quantitative PCR was performed using the Applied Biosystems Assay-on-DemandTM Gene Expression Products protocol as previously described (28). In brief, total RNA was isolated from the collected brain regions using the Tri Reagent protocol (Sigma). Concentrations of RNA and OD 260/280 ratios were determined by spectrometry (Hitachi U-2001) and RNA integrity was confirmed by resolution on a formaldehyde agarose gel. Before qPCR, RNA samples were treated with DNase I (Ambion) to remove potential DNA contamination. Total RNA was reverse transcribed with Moloney Murine Leukemia Virus reverse transcriptase (MMLV-RT) for 1 h at 42°C with random decamers following the RT protocol provided in the RETROscript kit, without heat denaturation of RNA (Ambion). Resultant first-strand cDNA was amplified by the Taqman Universal PCR Master Mix with sequence-specific primers and the FAM-labeled Taqman MGB probe assay mix. The assay IDs for the target genes in the assay mix were: IL-6 (Mm00446190_m1), IL-1ß (Mm00434228_m1), and TNF (Mm00443258_m1), and for the endogenous control glucose-3 phosphate dehydrogenase (G3PDH, Mm99999915_g1). Fluorescence was determined on an ABI PRISM 7700 sequence detection system (Applied Biosystems). PCR reactions were performed under the following conditions: 50°C for 2 min, 95°C for 10 min, followed by 40 cycles of 95°C for 15 s and 60°C for 1 min. Data were normalized with the G3PDH endogenous control and analyzed using the comparative threshold cycle method with results expressed as fold difference (28).
Statistical analysis. All data were subjected to the Shapiro-Wilk test using SAS® statistical software to ensure a normal distribution. Observations > 3 interquartile ranges from the 1st or 3rd quartiles were considered outliers and not included in subsequent analysis. Remaining data were subjected to 1-, 2-, or 3-way ANOVA using the PROC General Linear Measures procedures of SAS®. Due to unbalanced data sets, post hoc Student’s t test using Fisher adjustment of least-squares means was employed to determine whether treatment means were significantly different from one another (P < 0.05). All data are presented as means ± SEM.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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-Tocopherol and GPX activity.
As anticipated, diet influenced plasma (P < 0.001) and brain (P < 0.03) -T and GPX activity (Fig. 1), whereas neither LPS nor its interaction with diet were significant. Specifically, both -T concentrations (Fig. 1B) and GPX activity (Fig. 1A) in plasma increased with each increment in dietary -T and selenium. In the brain, however, -T and GPX activity were lower in mice fed the low diet than in the other groups, which did not differ from one another (Fig. 1).
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-T and selenium continued to display substantial LPS-induced reductions in social exploration at 4 h, whereas mice fed diets either adequate or high in -T and selenium began to recover and displayed smaller LPS-induced reductions in social exploration (P 
0.01). Although social behavior of LPS-injected mice returned to baseline by 8 h, changes in body weight persisted through the 8- and 24-h time points (Fig. 2B). Of note, aged mice fed the low diet lost more weight 8 h after injection of LPS than mice fed either adequate or high levels of -T and selenium, and the difference from mice fed the high diet persisted at 24 h (Fig. 2B). Neither social behavior nor body weight of saline-injected mice was affected by diet. Therefore, for clarity of presentation the mean for mice fed all 3 diets is shown in Figure 2.
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mRNA (Table 4) levels in each brain region evaluated at 2 h after injection. With only a few exceptions, diet did not affect LPS-induced cytokine expression in brain. Aged mice fed the high diet and injected with LPS had more IL-1ß mRNA in the striatum (Table 2) and more TNF mRNA in the cerebellum (Table 4) than mice fed either the adequate or low diet.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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-T and selenium affects the behavioral response to LPS in aged mice. The most important novel finding of this study is that aged mice fed a diet either adequate or high in -T and selenium had enhanced recovery from LPS-induced sickness compared with mice fed a diet low in -T and selenium. This suggests that ensuring adequate antioxidant intake in the elderly may improve their general health by reducing the time required to recover from infection.
Evidence exists to support a beneficial role for antioxidants in relieving LPS-induced cytokine production and changes in behavior. Kheir-Eldin et al. (34) found that combined -T and selenium treatment provided the greatest protection against brain oxidative stress induced by LPS administration compared with N-acetylcysteine and ß-carotene. The synergism between -T and selenium appears to result from their ability to modulate different forms of oxidative stress. -Tocopherol is a major lipid-soluble antioxidant that prevents lipid peroxidation of membranes, whereas selenium is required by a large family of selenoproteins, i.e., glutathione peroxidases and thioredoxin reductases, that functions to reduce hydroperoxides. Importantly, dietary supplementation of -T in rats increased brain concentrations (35) and the -T transport protein was recently localized in the cerebral cortex to the Bergman glial cells within the Purkenje cell layer (36).
Our goal was to determine whether starting dietary antioxidant intervention in older adult mice could modulate their behavioral response to low-level immune stimulation. We chose to start dietary intervention with -T and selenium at 18 mo of age because characterization of our in-house aging BALB/c mouse colony demonstrated that the greatest increase in brain lipid peroxidation occurs between 18 and 21 mo of age (37). The fact that -T and selenium do not prevent sickness behavior induced by LPS was not surprising because previous work from our laboratory found similar results in adult mice (22). However, although sickness behavior was clearly modulated by diet at 4 h in adult mice (22), aged mice in this study did not appear to benefit from dietary -T and selenium above adequate levels. In addition, because Han et al. (32) found supplemental levels of -T beneficial for aged mice infected with influenza virus, there may be differential effects of -T that depend upon the type of immune challenge. Importantly, we also report here that dietary -T and selenium reduce the severity of weight loss induced by LPS, which is consistent with a previous report (32) showing that improving -T status reduced influenza-induced body weight loss in aged mice. Dietary -T and selenium dose dependently increased plasma -T concentrations and GPX activity, respectively. However, brain -T levels and GPX activity were maximized by the diet adequate in -T and selenium. Because there was no further improvement in recovery of social exploration in mice fed the high diet compared with those fed the adequate diet, it is possible that the behavioral effects of -T and selenium are limited by their ability to enter or be retained in the brain tissue of aged mice.
Several reports indicated that -T and selenium have novel functions stemming from their traditional roles as biochemical and enzymatic antioxidants, respectively. For example, -T inhibits protein kinase C, which in turn inhibits formation of the NADPH oxidase complex, thereby reducing ROS formation (38). Macrophages express the oxidized lipid scavenger receptor CD36; -T can downregulate CD36 mRNA and protein expression in macrophages, thereby inhibiting uptake of oxidized LDL (39). Furthermore, -T and selenium can regulate activator protein (AP)-1– and NFB-dependent (40–44) cytokine gene transcription. Because cytokines are critical regulators of sickness behaviors (9,45–47), we hypothesized that -T and selenium might alter sickness behavior in aged mice by decreasing the de novo transcription of IL-1ß, IL-6, or TNF inflammatory cytokines in response to LPS.
Although LPS upregulated cytokine mRNA in each brain region analyzed, there was no consistent inhibition by dietary -T and selenium. In fact, the only significant responses due to diet were an upregulation of IL-1ß in striatum and TNF in cerebellum in mice fed the high diet compared with mice fed either the adequate or low diet. Although these data do not appear to directly support our hypothesis, they also do not totally discount it. For example, we chose to collect brain regions at the 2-h time point because it represents the peak of inhibited social exploration. In retrospect, however, it is conceivable that dietary -T and selenium modulated cytokine production later because they did not prevent sickness, but rather enhanced recovery from LPS. Furthermore, there are reports of antioxidant-induced upregulation of NFB and AP-1 transcription of genes in liver (48) and neurons (49). In those experiments, emphasis was placed on the cell survival genes transcribed by NFB and AP-1; therefore, it is possible that -T and selenium modulate cytokine-independent pathways to enhance recovery from LPS.
Taken together, these data indicate that -T and selenium interact with the immune and central nervous system to modify LPS-induced sickness behavior in aged mice. The effects observed here indicate that ensuring an adequate intake of -T and selenium may be more important than emphasizing mega-dose supplementation of these antioxidants. Accordingly, Meydani and colleagues recently found that elderly nursing-home residents who received 200 IU -T/d for 1 y had a lower incidence of common colds and fewer reports of one or more upper respiratory infections than an age-matched placebo-treated group (50). It is important to recognize the potential effect of dietary factors on immune function of the elderly considering their inability to maintain adequate nutrient intakes as well as recover from common infections.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Supported by National Institutes of Health grants AG16710 and MH069148. B.M.B is supported in part by a Retirement Research Foundation Scholarship and J.P.G is supported by a Ruth L. Kirchstein National Research Service Award Postdoctoral Fellowship.
3 Present address: Rush University Medical Center, Department of Neurology, Chicago, IL 60612.
5 Abbreviations used: AP, activator protein; -T, -tocopherol; G3PDH, glucose-3 phosphate dehydrogenase; GPX, glutathione peroxidase; IL, interleukin; NF, nuclear factor; PAMP, pathogen-associated molecular pattern; ROS, reactive oxygen species; TNF, tumor necrosis factor.
Manuscript received 11 December 2004. Initial review completed 9 February 2005. Revision accepted 28 February 2005.
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