Clinical Immunology and Immunopathology
Brief communicationEffect of calorie restriction on the production and responsiveness to interleukin 2 in (NZB × NZW)F1 mice
Abstract
Calorie restriction preserves the immunologic functions of the autoimmune prone B/W mice and prolongs their life. B/W mice fed normal calories were deficient in production of Interleukin 2 (IL-2) and in responses to exogenous IL-2 after 5 months of age. Calorie restriction leads to the preservation of IL-2 production in the spleen cells of these animals. Furthermore, these calorie-restricted mice responded vigorously to exogenous IL-2 in the thymocyte proliferation assay while mice fed a normal calorie diet lost much of the ability of their thymocytes to respond to IL-2. Whether calorie restriction in preserving the immune function of B/W mice involves IL-2 production and/or IL-2 response requires further analysis.
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Malnutrition leads to immune dysfunction with greatly increased morbidity. However, restrictive dietary regimens are also known to preserve immune function in autoimmune-susceptible mice. The macrophage (M∅) is central to both immune effector and autoregulatory functions and is critical to host-defense mechanisms. The aim of this study was to investigate the effect of calorie restriction on M∅ functions in mice. Female, 6- to 8-wk-old, Swiss Webster mice were randomized to ad libitum feeding for 7 or 21 d (n = 10 mice/group), restricted feeding (13.5 to 14.0 g/cage/d; n = 10) for 7 d, or restricted feeding (16.5 to 17.0 g/cage/d; n = 10) for 21 d. These restrictions were equivalent to a decrease in calorie intake of 21.9% and 5.1%, respectively, over 7 and 21 d. All mice were allowed free access to water. On days 8 and 22, respectively, the mice were killed, and peritoneal M∅s were isolated by lavage and adhered to 96-well polystyrene tissue-culture–treated plates. After stimulation with lipopolysaccharide, supernatant prostaglandin E2 and interleukin-6 levels were measured by enzyme-linked immunosorbent assay. Supernatant NO2− in response to stimulation with lipopolysaccharide and interferon-γ was determined by the Greiss reaction. Prostaglandin E2 production was significantly elevated in peritoneal M∅s from the calorie-restricted mice compared with the ad-libitum–fed mice after 7 d. After 21 d, production of both prostaglandin E2 and nitric oxide was significantly increased (P < 0.05) in peritoneal M∅s from the restricted mice compared with the ad-libitum–fed mice. These results indicate that calorie restriction influences immune function by altering prostaglandin E2 and nitric oxide generation by M∅s.
Dietary (n-6) and (n-3) fatty acids and energy restriction modulate mesenteric lymph node lymphocyte function in autoimmune-prone (NZB x NZW)F1 mice
2000, Journal of NutritionWe previously showed that dietary fish oil (FO) and energy restriction (R) have beneficial anti-inflammatory properties in the peripheral blood and spleens of (NZB × NZW)F1 (B/W) lupus-prone mice. Furthermore, unsaturated fatty acids also were shown in the past to influence mesenteric lymph node (MLN) lymphocyte function in healthy young rats. The MLN play a pivotal role in mediating food allergy. To date, the effect of R on intestinal immunity is not well understood; therefore we determined the effect of diet on MLN lymphocyte function. Mice were given either free access to a 5 g/100 g corn oil (CO) or fish oil (FO) diet or the same corn oil (CR) or fish oil (FR) diets restricted to 60% of the intake of the control group. At the age of 4 (young) and 8 (old) mo, MLN lymphocytes were isolated and B- (CD19+) and T-lymphocyte subsets (CD4+ and CD8+) were determined by flow cytometry. Additional MLN lymphocytes were placed in culture with or without concanavalin A and culture supernatants collected after 72 h for cytokine and immunoglobulin (Ig) quantitation by ELISA. Aging significantly (P < 0.05) decreased both CD4+ and CD8+ T-lymphocytes. Spontaneous and activation-induced interleukin-4 (IL-4), IL-10, and interferon-γ secretion were greater while IL-2 was lower in CO-fed old mice compared to CO-fed young mice. In contrast, CR or FO alone partially blunted the age-dependent alterations in T-lymphocyte ratios including cytokine and Ig secretion, whereas the FR diet significantly (P < 0.005) normalized the accelerated aging effects on these immune variables. We show for the first time that FR is a far more potent anti-inflammatory therapy than either CR or FO alone in modulating MLN lymphocyte function.
The increase in the induction of IL-2 expression with caloric restriction is correlated to changes in the transcription factor NFAT
1997, Cellular ImmunologyThe objective of this study was to determine if the increase in the induction of interleukin-2 (IL-2) expression with caloric restriction correlates with changes in binding activity of the IL-2-specific transcription factor NFAT (nuclear factor of activated T cells) and/or the ubiquitous transcription factor AP-1 in T cells from male Fischer 344 rats. Splenic T cells were isolated from young (6-month) and old (24-month) rats fedad libitumand from old (24-month) rats fed a restricted diet (40% caloric restriction) that began at 6 weeks of age. T cells were stimulated with concanavalin A (Con A) and the expression of IL-2 and the DNA binding activity of the transcription factors NFAT and AP-1 were measured in these cells. We found that the induction of IL-2 activity and mRNA levels decreased with age and that caloric restriction significantly (P< 0.05) reduced the age-related decline in IL-2 expression. The ability of nuclear extracts from T cells isolated from old rats fedad libitumand restricted old rats to bind to the NFAT oligonucleotide or AP-1 oligonucleotide decreased with age. Caloric restriction significantly (P< 0.05) reduced the age-related decline in NFAT but had no significant effect on AP-1 binding activity. We also measured the induction of c-fos and c-jun expression by Con A in T cells from young and old rats fedad libitumor caloric-restricted diet. The induction of c-fos protein and mRNA levels but not c-jun protein or mRNA levels decreased significantly with age. Caloric restriction significantly (P< 0.05) reduced the age-related decline in c-fos expression but had no significant effect on c-jun expression. Therefore, the increase in IL-2 expression with caloric restriction correlates with an increase in binding activity of transcription factor NFAT and an increase in the expression of c-fos, which is a component of the NFAT–protein complex.
The effect of age on the expression of interleukin-2
1996, Mechanisms of Ageing and DevelopmentInterleukin-2 (IL-2) is a growth promoting cytokine that has received a great deal of attention over the past decade with respect to aging and cancer. It is produced primarily by helper T cells and regulates the growth and function of various cells that are involved in cellular and humoral immunity. The expression of IL-2 has been found to decrease with age in humans and rodents. The decline in IL-2 production has been shown to parallel the age-related decrease in immunologic function. Several studies indicate that treatment of lymphocytes from old subjects with exogenous IL-2 or infusion of IL-2 into old animals partially or completely restores some of the immune functions that decline with age. The age-related decline in IL-2 production has been shown to arise from a decline in IL-2 transcription, and a recent study suggests that the transcription factor NFAT (nuclear factor of activated T cells) may play a role in the decline in IL-2 transcription.
Age-associated changes in mitogen-induced lymphoproliferation and lymphokine production in the long-lived brown-norway rat: effect of caloric restriction
1995, Mechanisms of Ageing and DevelopmentWe have previously demonstrated that age-related declines in Concanavalin A (ConA), induced proliferation and lymphokine production, occur in ad-libitum fed Brown Norway (AL BN) rats. Since caloric restriction (CR) extends lifespan, we expected that the age related changes in immune parameters would be delayed by CR. CR does act to delay age-related changes in proliferation in response to ConA. In addition, CR postpones the plateau in ConA induced interferon (IFN) production seen after 23 months of age in AL rats. However, CR does not postpone the age-related decline in ConA induced interleukin-2 (IL-2) production. Therefore, ConA induced IFN production maybe a good candidate as an early marker of physiologic aging, while ConA induced proliferative response is a possible candidate for a marker of late stages of aging.
Effect of dehydroepiandrosterone on mitogen-induced lymphocyte proliferation and cytokine production in young and old F344 rats
1995, Immunology LettersThe steroid hormone intermediate, dehydroepiandrosterone (DHEA), has been proposed as a therapeutic agent for the treatment of immunosenescence in mouse model. In the present study, the in vitro effect of DHEA on mitogen-induced lymphocyte proliferation and cytokine production was evaluated in a rat model. Spleen lymphocytes were isolated from young (4–6 months) and old (24–26 months) F344 rats and were incubated with DHEA for 30 min. The induction of lymphocyte proliferation, interleukin-2 (IL-2), and interferon-gamma (IFN-γ) production by concanavalin A (Con A) was measured in a culture medium supplemented with either fetal calf serum (FCS) or with serum-free medium (Nutridoma-SR, N-SR). The induction of lymphocyte proliferation and IL-2 production by Con A decreased significantly with age, whereas induction of IFN-γ increased with age. Treatment of lymphocytes with DHEA did not significantly alter Con A-induced proliferation or the production of IL-2 or IFN-γ by spleen lymphocytes isolated from either young or old rats. These data indicate that in vitro DHEA treatment appears to have no immunomodulatory effect on the age-related changes in mitogen-induced proliferation or cytokine production in rat lymphocytes.