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a Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging, Sackler Graduate School of Biomedical Science, Tufts University, Boston, Massachusetts
b Department of Pathology, Sackler Graduate School of Biomedical Science, Tufts University, Boston, Massachusetts
Simin Nikbin Meydani, Nutritional Immunology Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, 711 Washington Street, Boston, MA 02111 E-mail: smeydani{at}hnrc.tufts.edu.
Decision Editor: Jay Roberts, PhD
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Abstract |
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) as well as the effect of IL-6 on the production of other M inflammatory products. Similar to the findings in humans, mouse age did not influence the level of IL-6 produced by M. These data suggest that in healthy subjects, increased production of IL-6 is not a normal consequence of aging. Previously reported higher IL-6 levels in elderly subjects might reflect an underlying, undiagnosed disease state. PGE2 and NO production were not affected by the addition of IL-6 to M from young mice or anti-IL-6 antibody to M from old mice. Thus, IL-6 does not appear to influence the M production of selected inflammatory molecules.
AGING is associated with dysregulation of the immune and inflammatory responses, including changes in the regulation and production of cytokines. Cytokines are essential for normal immune function. However, certain cytokines, when produced at inappropriate levels, can initiate and mediate many of the metabolic and pathological changes observed in infection, trauma, chronic inflammatory diseases, and autoimmune conditions. One such cytokine is interleukin-6 (IL-6), which is produced by both lymphoid and nonlymphoid cells. It is a multifunctional cytokine that plays a role in a wide range of immune responses including acute-phase reactions and hemopoiesis. IL-6 production is normally low, and its serum levels are often undetectable in the absence of disease. High levels of IL-6 have been reported in the plasma and serum of aged mice and humans (1)(2). Additionally, in vitro production of IL-6 by unstimulated splenocytes was reported to be higher in old mice than in young mice (1). These reports have led to the conclusion that dysregulation of IL-6 production is a normal consequence of aging. However, most human studies have used volunteers that reported themselves to be healthy, whereas murine studies in general have discarded animals with obvious lesions. IL-6, arguably more than any other cytokine, is a potential marker for a variety of diseases, the incidence of which increase with age (3). Therefore, we investigated the effect of age on IL-6 serum levels and constitutive and stimulated peripheral blood mononuclear cells (PBMC) production in a carefully screened population of healthy human subjects. Additionally, because macrophages (M) are key producers of IL-6 (4)(5) and because it has been suggested that any age-related change in IL-6 production is due to changes in M, to determine age-related changes in IL-6 secretion we used purified in vitro cultures of primary resident murine peritoneal M.
It has been hypothesized that many of the changes in immune function seen with advanced age may be the consequence of increased IL-6 production (1). M production of prostaglandin E2 (PGE2) and nitric oxide (NO) has been shown to increase with age and to contribute to the decline in T-cell function with age (6)(7)(8)(9). IL-6 has been reported to regulate in vitro PGE2 production by selected cell lines (10). Sawada and colleagues (11) reported that expression of inducible NO synthase, the enzyme that catalyses the synthesis of NO in M, was transcriptionally activated by IL-6 in murine myeloid M1 cells. Therefore, the second specific aim of this study was to determine the effect of IL-6 on the production of PGE2 and NO by resident peritoneal M.
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Materials and Methods |
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Blood Collection and PBMC Separation
Blood was collected from subjects at different times of the year to eliminate seasonal effects. Subjects were asked to fast for 14 hours prior to having their blood drawn. Blood was collected in foil-wrapped vacutainer tubes with sodium heparin and was maintained at room temperature until processed. Blood was drawn from each subject once a week for 3 weeks. Results obtained from the three blood draws were averaged to account for day-to-day variation in cytokine levels.
PBMC were isolated from whole blood by Ficoll-paque (Pharmacia Biotech, Piscataway, NJ) density-gradient centrifugation as previously described (12). PBMC were cultured in endotoxin-free RPMI 1640 (Sigma, St. Louis, MO) media supplemented with 25 mmol/l HEPES, 2 mmol/l glutamine (BioWhittaker, Walkerville, MD), 100 units penicillin per ml, and 100 µg streptomycin per ml (Gibco BRL, Grand Island, NY) (complete RPMI). Additionally, complete RPMI was supplemented with 10% fetal calf serum or autologous heat-inactivated plasma. To determine the amount of lL-6 produced by PBMC, cells (1.0 x 109 cells/l) were cultured in the presence or absence of phytohemagglutinin (PHA; 10 mg/l) or concanavalin A (ConA; 10 mg/l) for 48 hours. IL-6 levels in cell-free supernatants were measured by enzyme-linked immunosorbent assay (ELISA, Genzyme, Cambridge, MA).
Mice
Over a 2-year period, 40 young (6-month-old) and 40 old (24-month-old) specific pathogen-free, male C57BL/6NCrlBR mice (Charles River, Wilmington, MA) fed Purina Mouse Chow (Ralston Purina, St. Louis, MO) and 40 young (6-month-old) and 40 old (24-month-old) C57BL/6NCrlBR mice fed a semipurified diet containing National Research Council-recommended levels of all nutrients were used in four separate experiments. Mice were individually housed in microisolator cages maintained in a controlled environment with a 12/12 hour light/dark cycle. Food and water were provided ad libitum. All conditions and handling of the animals were approved by the Animal Care and Use Committee of the JM USDA-HNRCA at Tufts University and followed the National Institutes of Health guidelines for the care and use of laboratory animals. Mice were sacrificed via CO2 asphyxiation. Mice exhibiting visible tumors were excluded from the study.
Peritoneal M Isolation
Peritoneal exudate cells were obtained by peritoneal lavage (13) with ice-cold Ca+1 and Mg+1 free HANKS media (Gibco). Peritoneal exudate cells were enriched for M by adherence (14). Cells were plated at 5 x 105 or 1 x 106 cells per well on 24-well tissue culture plates (Falcon Labware, Lincoln Park, NJ) in endotoxin-free RPMI 1640 media supplemented with 5% fetal calf serum, 25 mmol/l HEPES, 2 mmol/l glutamine, 100 units penicillin per ml, and 100 µg streptomycin per ml. Peritoneal M were allowed to adhere for 2 hours at 37°C in a 5% CO2 incubator at which time nonadherent cells were removed by vigorous washing. Cells were cultured in complete RPMI with and without lipopolysaccharide (LPS; 5 µg/ml for 48 hours). Cell-free supernatants were collected and stored at -70°C for later analysis.
Effect of IL-6 on M Production of PGE2 and NO
After enrichment, peritoneal M from old mice were incubated in medium containing either anti-IL-6 antibody (1, 5, or 10 µg/ml) (PharMingen, San Diego, CA) or isotype control antibody (1, 5, or 10 µg/ml) (Genzyme) with and without LPS (5 µg/ml). Next, M from young mice were incubated in medium containing recombinant murine IL-6 (Genzyme) with and without LPS (5 µg/ml). After 24 hours, supernatants were harvested, and cell-free supernatants were stored at -70°C until analysis for IL-6, PGE2, and NO.
IL-6, PGE2 , and NO Production
Human (Genzyme) and murine (PharMingen) IL-6 was quantitated by ELISA. Cytokine concentration was determined by comparison with a standard curve generated from serial dilutions of purified recombinant mouse (PharMingen) or human (Genzyme) IL-6.
PGE2 was analyzed by radioimmunoassay. The method for PGE2 analysis was based on the procedure described by McCosh and colleagues (15). The details of antibody specificity and cross-reactivity have been published (16).
NO production was determined by measuring the stable end product of NO metabolism, nitrite, by the colorimetric Griess reaction (17). Culture supernatant (100 µl) was mixed with an equal volume of Griess reagent and incubated at room temperature for 15 minutes. The absorbance was measured at 550 nm and compared with a standard curve generated from serial dilutions of NaNO2 in complete RPMI. The standard curve was linear from 3 to 24 µmol/l.
Statistical Analysis
Human data were tested for normality with the Wilk-Shapiro test. Data from the three separate blood draws were averaged, and their mean was used in the analysis. Because the data were not normally distributed, the two-sample Wilcoxon Mann-Whitney rank sum test was used to determine differences in IL-6 production between age groups. Data are reported as median and range or mean ± SE. Significance was set at p < .05. SAS Statistical System 7.0 (Cary, NC) was used for these calculations. NQuery 2.0 (Statistical Solutions, Saugus, MA) was used to determine the power of the tests to detect differences in IL-6 levels between young and elderly subjects with a Wilcoxon Mann-Whitney rank sum test with a .05, two-sided significance level.
The murine data addressing the age effect on IL-6 production was analyzed by analysis of variance (ANOVA) where an experimental date was used to block the data. Because an experiment by outcome (IL-6 level) interaction did occur, each of the four independent experiments was analyzed for age differences in IL-6. Additionally, the mean IL-6 values from all four experiments were tested for differences between age groups by Student's t test for normally distributed parameters and by Wilcoxon signed rank test for data that was not normally distributed using the SYSTAT statistical package (Systat, Inc, Evanston, IL). The mouse data addressing the influence of IL-6 on PGE2 or NO production were first analyzed to confirm whether age differences in IL-6, PGE2, and NO did or did not occur. This was done using a two-factor ANOVA. The effect of treatment within an age group was determined by Student's t test. Data are reported as mean ± SE. Significance was set at p < .05.
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Results |
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Effect of Age on IL-6 Secretion by M From Mice
Macrophages are a major source of IL-6 in freshly isolated immune cell preparations (5)(18). To determine whether M demonstrated age-related changes in IL-6 secretion, we examined purified in vitro cultures of primary resident peritoneal M from mice. Over a 2-year period, four independent experiments were done. When the results from all experiments were combined, mouse age did not affect unstimulated (control) IL-6 production by M (Fig. 4a). However, when data from each independent experiment were analyzed separately, unstimulated IL-6 production was higher (p < .05) by resident peritoneal M from old compared with young mice in one of the four experiments (Fig. 4b), while no age-related differences were found in the other three. The level of unstimulated IL-6 secreted in this particular experiment was higher than that of the other three experiments. Although mice were excluded if lesions were observed at the time of sacrifice, a more extensive histological examination of the old mice revealed that the majority of mice used to determine IL-6 production in the experiment that showed an increased IL-6 level had a higher than normal lesion load compared with a control population (19). Concurrent with the high level of spontaneous IL-6 production seen in this study, spontaneous production of PGE2 was also high. Thivierge and Rola-Pleszczynski (20) have shown that PGE2 can increase the production of IL-6 by M.
LPS stimulation induced M to secrete even higher levels of IL-6 (Fig. 4a and Fig. 4b); however, there was no statistically significant difference in LPS-stimulated IL-6 production between age groups from any of the experiments.
Effect of IL-6 on Murine M Production of Other Inflammatory Molecules
In concurrence with other investigators, we have reported that M production of PGE2 and NO increases with age (8)(9)(21). It has been suggested that age-related increases in IL-6 levels contribute to this finding. To test this hypothesis, we added antibody against IL-6 to M cultures from old mice to determine the effect of lowering the level of IL-6 on PGE2 production in old mice. Additionally, we added recombinant IL-6 to M cultures from young mice to determine the effect of increasing IL-6 levels on PGE2 production of young mice. Similar to previously published data by our laboratory and others, murine M from either old (Table 2 ) or young (Table 3 ) mice produced low levels of PGE2 and NO in the absence of stimuli (medium control). In the absence of an additional stimulus, addition of recombinant IL-6 to M from young mice (Table 3 ) or neutralizing antibody against IL-6 to M from old mice (Table 2 ) did not change (p > .05) this low level of unstimulated PGE2 or NO production by M. As expected, the addition of LPS to the culture medium stimulated M from old (p < .05) (Table 2 ) and young (p < .05) mice (Table 3 ) to secrete increased levels of PGE2 and NO compared with cultures containing medium only. Confirming our previous findings, LPS-stimulated M production of PGE2 and NO was higher in M from old compared with M from young mice (21.1 ± 4 vs 12.5 ± 3.1 µmol/l for PGE2, p < .05, and 8.2 ± 2.9 vs 3.1 ± 2.2 µmol/l for NO, p < .05 in old and young mice, respectively) (Table 2 and Table 3 ).
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from old mice would affect the age-related changes in PGE2 and NO production, IL-6 neutralizing antibody was added to cultures containing old M. Addition of the IL-6 neutralizing antibody to LPS-stimulated M from old mice decreased (p < .05) IL-6 levels by 50% to 70% (data not shown). Lowering the level of IL-6, however, had no effect on PGE2 (p > .05) or NO (p > .05) production (Table 2 ).
In a parallel experiment, addition of rIL-6 to LPS-stimulated M from young mice increased (p < .05) the IL-6 levels in the stimulated cultures between 20% (low) and 40% (high) (data not shown) (Table 3 ) but did not affect PGE2 or NO production in young mice (Table 3 ).
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Discussion |
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Changes in the regulation and/or production of the cytokine IL-6 is one alteration that may have a great impact on immunity due to the wide variety of functions and cell types this cytokine affects (24). IL-6 has been shown to induce fever, regulate the acute-phase response, and promote differentiation and/or activation of T cells, B cells, and M (3)(5)(24). Dysregulation of IL-6 expression has been implicated in the pathogenesis of various diseases, including multiple myeloma, lymphoma, rheumatoid arthritis, and cardiac myxoma. In most conditions involving dysregulated IL-6 production, the mechanism(s) are not known (3)(5)(24).
Because of its central role in modulating immunity, IL-6 production is tightly regulated, and multiple mechanisms of IL-6 gene regulation exist (3). Therefore, under steady-state conditions, circulating IL-6 levels are low. In this study, the majority of subjects in both age groups had low IL-6 levels. Other researchers have hypothesized that age-related changes in the endocrine system somehow "relax" the strict control over IL-6 expression, resulting in its increased production with age (1)(2)(25). However, we found no difference in the average circulating levels of IL-6 between the healthy young and elderly human subjects. While these data agree with those of Peterson and colleagues (26), they contradict other human studies, which have reported higher levels of plasma/serum IL-6 in elderly subjects compared with young controls (1)(2)(4). Nor did we find an effect of age on constitutive IL-6 production by PBMC from the same individuals. Fagiolo and colleagues (24) also reported no effect of age on unstimulated PBMC IL-6 secretion in humans. However, Daynes and colleagues (1) reported higher constitutive IL-6 production by PBMC in elderly than in young subjects. One of the largest studies to examine the effect of age on constitutive IL-6 production by PBMC is that of Roubenoff and colleagues (27). They reported lower unstimulated IL-6 production by PBMC from young subjects compared with those of older subjects. However, the higher IL-6 levels in elderly subjects correlated with higher C-reactive protein (CRP) levels, an indicator of inflammation. Furthermore, the age difference in IL-6 was more pronounced in those with higher CRP levels. It is possible that higher IL-6 values lead to higher CRP levels. Roubenoff and colleagues (27) suggested that IL-6 elevation is related to both age and inflammation and may not be solely a phenomenon of advancing age.
Our data support this conclusion. The main difference between the current study and others is the health of the subjects. The elderly subjects in our study were stringently selected for good health. Although all the volunteers in the study by Roubenoff and colleagues (27) were ambulatory, the authors indicated that subjects taking medications and those with a variety of chronic illnesses were not excluded. In the study by Daynes and colleagues (1), because subjects were considered healthy by "self-report," their true health status cannot be ascertained. In the study by Mysliwska and colleagues (28), health status was graded according to the criteria of the Senieur protocol. Whereas increased levels of nonstimulated IL-6 were reported in this study, the level of IL-6 strictly correlated with individual health status; those with the best health status produced the lowest IL-6 (28). Interestingly, of the 50 elderly volunteers (men and women) who participated in this study, only 8 (incidentally, all female) fit the profile for "healthy." Thus, IL-6 may be elevated in most elderly persons due to the presence of disease.
A second possible explanation for the lack of age difference in this study is that an effect of age would have been demonstrated had more subjects, particularly young subjects, been used. There were 21 subjects in the young group and 26 subjects in the elderly group. Power analysis for a Wilcoxon (Mann-Whitney) rank-sum test with a .05 two-sided significance level was performed using the nQuery Advisor 2.0. Because the nQuery software could not compute the power for unequal samples sizes, we computed the effect size for equal sample sizes of 21 and 26 that can be detected with a power of .80; the actual effect size will clearly be between the lower and upper effect sizes. For sample size 21 in each group, the results indicate 80% power to detect a probability of .75 that an observation in the young group is less than an observation in the elderly group; for a sample size of 26 in each group, the results indicate 80% power to detect a probability of .724 that an observation in the young group is less than an observation in the elderly group. Because sample sizes are unequal, the actual effect size (i.e., the probability that an observation in the young group is less than an observation in the elderly group) is somewhere between .724 and .75. In the current study, 30% of the healthy young subjects had greater than 100 pg/ml of IL-6 in their serum. Two young individuals had very high (>1000 pg/ml) IL-6 levels. These individuals maintained their high IL-6 levels throughout the three blood draws, thus validating the result. Other studies (1)(2) reported that almost all the young individuals tested had low levels of IL-6 in their serum. It is possible that this greater variability in IL-6 levels within the young group might have reduced the statistical detectability of a difference between the two age groups. However, exclusion of the two subjects with high IL-6 levels did not change the results. Our conclusion is supported by the finding that in contrast to the results found in the young group, the median IL-6 serum levels from the elderly subjects in this study were lower than those previously reported (1). The majority of the elderly subjects had very low IL-6 levels, and only 38% had IL-6 levels greater than 100 pg/ml, indicating that in healthy elderly persons, IL-6 is not necessarily high.
Similar to findings in humans, an age-related increase in IL-6 production by murine cells has been reported (1). However, our mouse M data concurs with and expands upon the human data: unstimulated production of IL-6 by peritoneal M was not affected by mouse age. Although the majority of immune cells can produce IL-6, M are reportedly the cell type that becomes dysregulated with age. Data to support this hypothesis are limited. Daynes and colleagues (1) reported that removing the adherent cell population from splenocytes of old mice resulted in reduced IL-6 production. However, in the current study, which utilized purified peritoneal M, no effect of age on constitutive IL-6 production was found. IL-6 was higher in old compared with young mice only in a subgroup of mice with high lesion load (19). It should be noted that this group of mice appeared to be physically healthy, and mice with obvious lesions had already been eliminated from the study (about 20%). However, further lesions were noted after necropsy. Few studies conduct extensive pathological examinations of the mice from which samples are collected, yet the majority of C57BL/6NIA mice over 24 months of age do exhibit some type of lesion when examined (19). Further studies are needed to determine the contribution of age-associated pathologies to the reported age-related increase in IL-6 production.
In addition to health differences, there are two other, albeit less plausible, reasons for differences in findings among studies: the methods used to measure IL-6 and the sex of subject/animal. Transport of IL-6 in blood is fundamental to the biology of this cytokine. Typically, IL-6 produced locally at sites of tissue damage makes its way into the bloodstream where it then elicits a systemic response. Recent evidence suggests that this transport is much more complex than previously thought. Multiple binding proteins can complex with IL-6 resulting in distinct classes of chaperoned IL-6 in human blood that appear to vary in their biological availability (29). Little is known about the effect of age or disease on IL-6 transport. Commercial ELISA and commonly utilized bioassays vary in their ability to distinguish free and bound IL-6 (29).
Barrat and colleagues (30) reported that the onset, magnitude, and kinetics of the age-related changes in cytokine production are parity and sex dependent. In late adulthood, murine IL-6 levels were higher in multiparous females than in males or females that had not reproduced (30). Therefore, the sex of the subjects could influence the levels of IL-6 reported. Additionally, Cheleuitte and colleagues (31) reported that women receiving hormone replacement therapy had lower unstimulated IL-6 production by bone marrow than did age-matched controls. In the current study, all subjects were males, while other studies have used mixed sex populations. However, some studies in which mixed sex populations were used report no influence of sex on IL-6 production (28)(32), but the lack of sex effect in these studies could be due to small sample size and thus low power to detect sex differences.
IL-6 is readily induced by infectious agents, LPS, and a variety of cytokines (5). Mice that can no longer produce IL-6 are more susceptible to bacterial infection. Elderly humans are also more susceptible to microbial infections than young humans. This declining resistance may be due to the inability of M, when challenged, to produce cytokines at an appropriate level. In the current study, murine macrophages stimulated with LPS and human PBMC cultured in FBS and stimulated with PHA retained the capacity to respond to an exogenous stimulus. Only PBMC cultured in autologous serum and stimulated with ConA were influenced by donor age, with PBMC from the elderly subjects producing less IL-6 than PBMC from the young subjects. The lower IL-6 production by PBMC from the elderly subjects compared with the young subjects in the presence of AP and not FBS might be due to the presence of protein(s) in the plasma of elderly persons, which can bind IL-6 and reduce its detectability by ELISA. Although the majority of studies reported no effect of age on IL-6 production by stimulated immune cells, Effros and colleagues (33) reported that IL-6 production by monocytes begins to decline once mice reach 24 months of age.
Whereas IL-6 is produced by lymphoid and nonlymphoid cells, accessory cells represent a major source of IL-6 in freshly isolated cell preparations (5). It has been suggested that the previously reported age-related changes in IL-6 production are due to changes in M production of IL-6 (1). No effect of age on murine M IL-6 production was seen in the current study. Furthermore, it has been hypothesized that increased IL-6 production by M contributes both to the age-related changes in T-cell function and M production of other soluble molecules, particularly PGE2 and NO (7)(9). We investigated this possibility by adding recombinant IL-6 to M from young mice. IL-6 concentrations in the supernatant significantly increased, but production of PGE2 and NO were not affected. Furthermore, when a neutralizing antibody against IL-6 was added to M from old mice, IL-6 levels in the supernatant significantly decreased, but PGE2 and NO production were not affected. Thus, IL-6 does not seem to be a major contributor to the age-associated increase in PGE2 and NO production (34). In conclusion, we found that circulating IL-6 levels and unstimulated secretion of IL-6 by PBMC does not change with age in humans or mice. The reported age-related increase in IL-6 production probably reflects an underlying, undiagnosed disease state. In addition, increased IL-6 production does not contribute to the age-related increase in PGE2 and NO production by murine M. Further work is needed to determine the underlying age-associated pathologies that contribute to higher IL-6 production.
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Acknowledgments |
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Received May 13, 1999
Accepted May 15, 2000
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in unextracted plasma, serum and myocardium. Prostaglandins. 12:471-486. [Medline]
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