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Time-restricted feeding (TRF) has emerged as a promising dietary approach for improving metabolic parameters associated with obesity. However, it remains largely unclear whether TRF offers benefits for obesity related to exposure to light at night. This study examined whether lean and obese mice under chronic light exposure could benefit from TRF intervention. Six-week-old C57BL/6 male mice were fed either a low-fat diet or a high-fat diet under a 12 h light/12 h dark cycle for 6 weeks. They were then divided into three subgroups: control light, chronic 24 h light, and chronic light with a daily 10 h TRF. Chronic light exposure led to increased weight gain and higher expression of inflammatory and fibrotic markers in the adipose tissue of both lean and obese mice. It also increased hepatic triglyceride content in mice, regardless of their weight status. TRF protected both lean and obese mice from weight gain, normalized inflammatory and fibrotic gene expression, and reduced adipose tissue collagen and liver triglyceride accumulation caused by light exposure alone or in combination with obesity. These results suggest that TRF could have clinical implications for preventing obesity associated with night shift work, regardless of current weight status.

Time-restricted feeding (TRF) has been shown to improve the disordered metabolic and immunologic functions associated with obesity, however little is known about its post-effects after the cessation of TRF practice. In the current study, we determined how long the effects of TRF persist, and whether the effects are tissue-dependent. There were four groups of mice in this study: overweight and obese mice were randomized into (1) TRF group (TRF for 6 weeks), (2) post-TRF group (TRF for 4 weeks and later ad libitum), (3) continuous ad libitum of high-fat diet (HFD-AL), and (4) the lean control-fed low-fat diet ad libitum. Blood, liver, and adipose tissues were collected to measure the metabolic, inflammatory, and immune cell parameters. The results showed that TRF withdrawal quickly led to increased body weight/adiposity and reversed fasting blood glucose. However, fasting insulin and insulin resistance index HOMA-IR remained lower in the post-TRF than in the HFD-AL group. In addition, TRF-induced reduction in blood monocytes waned in the post-TRF group, but the TRF effects on mRNA levels of proinflammatory immune cells (macrophages Adgre1 and Itgax ) and cytokine ( Tnf ) in adipose tissue remained lower in the post-TRF group than in the HFD-AL group. Furthermore, the TRF group was protected from the down-regulation of Pparg mRNA expression in adipose tissue, which was also observed in the post-TRF group to a lesser extent. The post-TRF animals displayed liver mass similar to those in the TRF group, but the TRF effects on the mRNA of inflammation markers in the liver vanished completely. Together, these results indicate that, although the lasting effects of TRF may differ by tissues and genes, the impact of TRF on adipose tissue inflammation and immune cell infiltration could last a couple of weeks, which may, in part, contribute to the maintenance of insulin sensitivity even after the cessation of TRF.

Time-restricted feeding (TRF) has emerged as a promising dietary approach in improving metabolic parameters associated with obesity, but its effect on immune cells under obesogenic condition is poorly understood. We conducted this study to determine whether TRF exerts its therapeutic benefit over obesity-induced myeloid cell production by analyzing hematopoietic stem and progenitor cells in bone marrow (BM) and immune cell profile in circulation. Male C57BL/6 mice were fed a low-fat diet (LFD) or high-fat diet (HFD) ad libitum for 6 weeks and later a subgroup of HFD mice was switched to a daily 10 h-TRF schedule for another 6 weeks. Mice on HFD ad libitum for 12 weeks had prominent monocytosis and neutrophilia, associated with expansion of BM myeloid progenitors, such as multipotent progenitors, pre-granulocyte/macrophage progenitors, and granulocyte/macrophage progenitors. TRF intervention in overweight and obese mice diminished these changes to a level similar to those seen in mice fed LFD. While having no effect on BM progenitor cell proliferation, TRF reduced expression of Cebpa , a transcription factor required for myeloid differentiation. These results indicate that TRF intervention may help maintain immune cell homeostasis in BM and circulation during obesity, which may in part contribute to health benefits associated with TRF., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflicted of interest., (Copyright © 2022 Kim, Lee, Lee, Nah, Yun, Wu and Pae.)

Background/objectives: Vitamin D is produced in the skin during sun exposure and is also ingested from foods. The role of vitamin D needs to be considered in the prevention and management of various diseases. Moreover, since the majority of Koreans spend their days indoors, becoming susceptible to the risk of vitamin D deficiency. The current study aims to prepare a basis for determining dietary reference intake of vitamin D in Korea, by reviewing the evidence against various diseases and risks., Materials/methods: Literature published in Korea and other countries between 2014 and 2018 was prioritized based on their study design and other criteria, and evaluated using the RoB 2.0 assessment form and United States Department of Agriculture Nutrition Evidence Library Conclusion Statement Evaluation Criteria., Results: Of the 1,709 studies, 128 studies were included in the final systematic analysis after screening. To set the dietary reference intakes of vitamin D based on the selected articles, blood 25(OH)D levels and indicators of bone health were used collectively. Blood vitamin D levels and ultraviolet (UV) exposure time derived from the Korean National Health and Nutrition Examination Survey were analyzed to establish the dietary reference intakes of vitamin D for each stage of the life cycle. The adequate intake levels of vitamin D, according to age and gender, were determined to be in the range of 5-15 μg/day, and the tolerable upper intake level was established at 25-100 μg/day., Conclusions: The most important variable for vitamin D nutrition is lifestyle. A balanced diet comprising foods with high contents of vitamin D is important, as is vitamin D synthesis after UV exposure. The adequate intake level of vitamin D mentioned in the 2015 Dietary Reference Intakes for Korean (KDRI) remained unchanged in the 2020 KDRI for the management of vitamin D nutrition in Koreans., Competing Interests: Conflict of Interest: The authors declare no potential conflicts of interests., (©2022 The Korean Nutrition Society and the Korean Society of Community Nutrition.)

Studies suggest that time-restricted feeding (TRF) may prevent obesity and its commodities. At present, little is known about how TRF impacts immune cells, and whether such an effect is linked to altered metabolic parameters under condition of a high-fat diet (HFD)-induced obesity. To address these issues, we conducted a study in which we determined whether TRF has therapeutic efficacy against weight gain, adiposity, as well as associated immune cell disturbance found in obese mice. Six-week-old male C57BL/6 mice were fed a low-fat diet (LFD) or HFD ad libitum for six weeks, after which time a subgroup of HFD mice was switched to the 10 h TRF paradigm (HFD-TRF) for additional eight weeks. We found that TRF intervention reduced HFD-induced weight gain. Even with comparable fat mass and mean adipocyte area, the HFD-TRF group had lower mRNA levels of proinflammatory cytokine Tnfα and chemokine Ccl8 , along with reduced numbers of adipose tissue macrophages (ATM), CD11c + ATM, and CD8 + T cell compared to the HFD group, while maintaining CD8 + to CD4 + ratio at levels similar to those in the LFD group. Furthermore, TRF intervention was effective in improving glucose tolerance and reducing HOMA-IR. Taken together, our findings suggest that TRF restores the obesity-induced alteration in immune cell composition, and this effect may in part contribute to health benefits (including insulin sensitivity) of practicing TRF.

The NLRP3 inflammasome is a caspase-1 containing multi-protein complex that controls the release of IL-1β and plays important roles in the innate immune response. Since NLRP3 inflammasome is implicated in the pathogenesis of a variety of diseases, it has become an increasingly interested target in developing therapies for multiple diseases. We reported the current study to determine how luteolin, a natural phenolic compound found in many vegetables and medicinal herbs, would modulate NLRP3 inflammasome in both the in vivo and in vitro settings. First, we found that a high-fat diet upregulated mRNA expression of NLRP3 inflammasome components Asc and Casp1 in adipose tissue of ovariectomized mice, which were greatly reduced by dietary supplementation with luteolin. Of note, Asc and Casp1 expression in adipose tissue correlated with mRNA levels of Adgre1 encoding F4/80, an established marker for mature macrophages. We also demonstrated that luteolin inhibited NLRP3 inflammasome-derived caspase-1 activation and IL-1β secretion in J774A.1 macrophages upon diverse stimuli including ATP, nigericin, or silica crystals. Luteolin inhibited the activation step of NLRP3 inflammasome by interfering with ASC oligomerization. Taken together, these findings suggest that luteolin supplementation may suppress NLRP3 induction and activation process and thus potentially would be protective against NLRP3-mediated inflammatory diseases., (Copyright © 2021. Published by Elsevier Inc.)

Vitamin D status has been implicated in obesity and adipose tissue inflammation. In the present study, we explored the effects of dietary vitamin D supplementation on adipose tissue inflammation and immune cell population, and the effects of in vitro 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) treatment on pro-inflammatory cytokine production by stromal vascular cells (SVCs) and adipocytes in lean and high-fat diet-induced obese mice. The results show that epididymal fat Mcp-1 and Rantes mRNA levels, which were higher in obese mice compared with lean mice, were significantly down-regulated by vitamin D supplementation. While obese mice had higher numbers of macrophages and natural killer (NK) cells within adipose tissue, these remained unaltered by vitamin D supplementation. In accordance with these in vivo findings, the in vitro 1,25(OH)2D3 treatment decreased IL-6, MCP-1, and IL-1β production by SVCs from obese mice, but not by adipocytes. In addition, 1,25(OH)2D3 treatment significantly decreased Tlr2 expression and increased mRNA levels of I κ ba and Dusp1 in SVCs. These findings suggest that vitamin D supplementation attenuates inflammatory response in adipose tissue, especially in SVCs, possibly through inhibiting NF-κB and MAPK signaling pathways in SVCs but not by the inhibition of macrophage infiltration., Competing Interests: The authors declare no conflict of interest.

Previously, we showed that loss of ovarian function in mice fed high-fat diet exacerbated insulin resistance and adipose tissue inflammation. In the current study, we tested whether consumption of luteolin, an anti-inflammatory flavonoid, could mitigate adipose tissue inflammation and insulin resistance in obese ovariectomized mice. Nine-week-old ovariectomized C57BL/6 mice were fed a low-fat diet, high-fat diet (HFD) or HFD supplemented with 0.005% luteolin (HFD+L) for 16 weeks. Results showed no difference in body weight or fat mass between mice fed HFD+L and those fed HFD. However, luteolin supplementation resulted in lower CD11c + macrophages in gonadal adipose tissue, as well as a trend toward lower macrophage infiltration. Luteolin supplementation also significantly lowered mRNA expression of inflammatory and M1 markers MCP-1, CD11c, TNF-α and IL-6, while maintaining expression of M2 marker MGL1. Consistent with this, the in vitro luteolin treatment, with or without the presence of estrogen, inhibited lipopolysaccharide-induced polarization of RAW 264.7 cells toward M1 phenotype. We further found that luteolin supplementation protected mice from insulin resistance induced by HFD consumption; this improved insulin resistance was correlated with reductions in CD11c + adipose tissue macrophages. Taken together, these findings indicate that dietary luteolin supplementation attenuates adipose tissue inflammation and insulin resistance found in mice with loss of ovarian function coupled with an HFD intake, and this effect may be partly mediated through suppressing M1-like polarization of macrophages in adipose tissue. These results have clinical implication in implementing dietary intervention for prevention of metabolic syndrome associated with postmenopause and obesity., (Copyright © 2019 Elsevier Inc. All rights reserved.)

It is well-established that the nutritional deficiency or inadequacy can impair immune functions. Growing evidence suggests that for certain nutrients increased intake above currently recommended levels may help optimize immune functions including improving defense function and thus resistance to infection, while maintaining tolerance. This review will examine the data representing the research on prominent intervention agents n-3 polyunsaturated fatty acids (PUFA), micronutrients (zinc, vitamins D and E), and functional foods including probiotics and tea components for their immunological effects, working mechanisms, and clinical relevance. Many of these nutritive and non-nutritive food components are related in their functions to maintain or improve immune function including inhibition of pro-inflammatory mediators, promotion of anti-inflammatory functions, modulation of cell-mediated immunity, alteration of antigen-presenting cell functions, and communication between the innate and adaptive immune systems. Both animal and human studies present promising findings suggesting a clinical benefit of vitamin D, n-3 PUFA, and green tea catechin EGCG in autoimmune and inflammatory disorders, and vitamin D, vitamin E, zinc, and probiotics in reduction of infection. However, many studies report divergent and discrepant results/conclusions due to various factors. Chief among them, and thus call for attention, includes more standardized trial designs, better characterized populations, greater consideration for the intervention doses used, and more meaningful outcome measurements chosen.

Loss of ovarian function, as occurs in menopause or after ovariectomy (OVX), is associated with insulin resistance. Adipose tissue inflammation is suggested to be a key component of obesity-induced insulin resistance in male rodents. However, little is known about the effect of OVX and diet on insulin resistance in association with immune homeostasis. Thus, we conducted this study to determine how high-fat diet (HFD) and OVX, alone or in combination, impacted adipose tissue inflammation and insulin resistance. Nine-week-old sham and OVX-treated C57Bl/6 mice were fed low-fat diet (LFD) or HFD (60%) up to 16 weeks. Glucose metabolism was assessed, and adipose tissue and spleen were characterized for tissue inflammation and immune cell populations. First, we found that HFD induced glucose intolerance in both OVX mice and, to a lesser extent, sham mice. OVX mice fed LFD showed no difference in glucose intolerance compared to sham mice. Additionally, OVX mice only when exposed to HFD displayed a proinflammatory profile in adipose tissue: increased macrophages together with dominant M1-like phenotype and also increased T cells, B cells and NK cells compared to those with intact ovarian function. Together, our findings indicate that loss of ovarian function coupled with an HFD intake promotes insulin resistance and adipose tissue inflammation by disturbing adipose tissue immune homeostasis. These findings have a clinical implication in the dietary guidance for menopausal women., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Vitamin D has an immunoregulatory effect on both innate and adaptive immunity. Contradictory results regarding vitamin D and natural killer (NK) cell functions have been reported with in vitro studies, but little is known about this in vivo. We investigated whether vitamin D levels (50, 1000 or 10,000 IU/kg of diet: DD, DC or DS) affect NK cell functions in mice fed a control or high-fat diet (10% or 45% kcal fat: CD or HFD) for 12 weeks. The splenic NK cell activity was significantly higher in the CD-DS group than the HFD-DS group, and the CD-DS group showed significantly higher NK cell activity compared with the CD-DD and CD-DC groups. However, no difference in NK cell activity was observed among the HFD groups fed different levels of vitamin D. The splenic population of NK cells was significantly higher in the CD-DS group than the HFD-DS group. There was no difference in the intracellular expression of IFN-γ and the surface expression of NKG2D and CD107a in NK cells by both dietary fat and vitamin D content. The splenic mRNA expression of Ifng and Ccl5 was significantly lower in the HFD groups compared with the CD groups, but there was no difference in the mRNA levels of Vdup1 and Vdr among the groups. Taken together, these results suggest that dietary vitamin D supplementation can modulate innate immunity by increasing NK activity in control mice but not in obese mice. This effect might be mediated through alternation of the splenic NK cell population., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The immune system undergoes some adverse alterations during aging, many of which have been implicated in the increased morbidity and mortality associated with infection in the elderly. In addition to intrinsic changes to the immune system with aging, the elderly are more likely to have poor nutritional status, which further impacts the already impaired immune function. Although the elderly often have low zinc serum levels, several manifestations commonly observed during zinc deficiency are similar to the changes in immune function with aging. In the case of vitamin E, although its deficiency is rare, the intake above recommended levels is shown to enhance immune functions in the elderly and to reduce the risk of acquiring upper respiratory infections in nursing home residents. Vitamin D is a critical vitamin in bone metabolism, and its deficiency is far more common, which has been linked to increased risk of infection as demonstrated in a number of observational studies including those in the elderly. In this review, we focus on zinc, vitamin E, and vitamin D, the 3 nutrients which are relatively well documented for their roles in impacting immune function and infection in the elderly, to discuss the findings in this context reported in both the observational studies and interventional clinical trials. A perspective will be provided based on the analysis of information under review., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Obesity-induced inflammation mediated by immune cells in adipose tissue appears to participate in the pathogenesis of insulin resistance. We show that natural killer (NK) cells in adipose tissue play an important role. High-fat diet (HFD) increases NK cell numbers and the production of proinflammatory cytokines, notably TNFα, in epididymal, but not subcutaneous, fat depots. When NK cells were depleted either with neutralizing antibodies or genetic ablation in E4bp4(+/-) mice, obesity-induced insulin resistance improved in parallel with decreases in both adipose tissue macrophage (ATM) numbers, and ATM and adipose tissue inflammation. Conversely, expansion of NK cells following IL-15 administration or reconstitution of NK cells into E4bp4(-/-) mice increased both ATM numbers and adipose tissue inflammation and exacerbated HFD-induced insulin resistance. These results indicate that adipose NK cells control ATMs as an upstream regulator potentially by producing proinflammatory mediators, including TNFα, and thereby contribute to the development of obesity-induced insulin resistance., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Profilin-1 (pfn) is a small ubiquitous protein that can bind to: (1) G-actin, (2) phosphatidylinositol 4,5-bisphosphate, and (3) a heterogeneous group of proteins harboring poly-l-proline stretches. Through these interactions, pfn integrates signaling from a diverse array of extracellular cues with actin cytoskeleton dynamics. Cumulating evidence indicates that changes in pfn levels are associated and may play a pathogenic role in such inflammatory diseases as atherosclerosis and glomerulonephritis. We recently demonstrated that high fat diet (HFD) increases pfn expression in the white adipose tissue (WAT), but not in the liver or the muscle. Pfn heterozygote mice (PfnHet) were protected against HFD-induced glucose intolerance, and WAT and systemic inflammation, when compared to pfn wild-type mice. In addition to blunted accumulation of macrophages and reduced "pro-inflammatory" cytokines, the WAT of PfnHet exhibited preserved frequency of regulatory T cells. These findings suggest that pfn levels in WAT-both adipocytes and hematopoietic-derived cells-can modulate immune homeostasis within the WAT and glucose tolerance systemically. Here, we review the interaction of pfn with his diverse array of binding partners and discuss mechanisms that may underlie the effects of pfn dosage on insulin sensitivity and metabolic inflammation.

Metabolic inflammation may contribute to the pathogenesis of obesity and its comorbidities, including type 2 diabetes and cardiovascular disease. Previously, we showed that the actin-binding protein profilin-1 (pfn) plays a role in atherogenesis because pfn heterozygote mice (PfnHet) exhibited a significant reduction in atherosclerotic lesion burden and vascular inflammation. In the current study, we tested whether pfn haploinsufficiency would also limit diet-induced adipose tissue inflammation and insulin resistance (IR). First, we found that a high-fat diet (HFD) upregulated pfn expression in epididymal and subcutaneous white adipose tissue (WAT) but not in the liver or muscle of C57BL/6 mice compared with normal chow. Pfn expression in WAT correlated with F4/80, an established marker for mature macrophages. Of note, HFD elevated pfn protein levels in both stromal vascular cells and adipocytes of WAT. We also found that PfnHet were significantly protected from HFD-induced glucose intolerance observed in pfn wild-type mice. With HFD, PfnHet displayed blunted expression of systemic and WAT proinflammatory cytokines and decreased accumulation of adipose tissue macrophages, which were also preferentially biased toward an M2-like phenotype; this correlated with preserved frequency of regulatory T cells. Taken together, the findings indicate that pfn haploinsufficiency protects against diet-induced IR and inflammation by modulating WAT immune homeostasis.

Consuming green tea or its active ingredient, epigallocatechin-3-gallate (EGCG), has been shown consistently to benefit the healthy functioning of several body systems. In the immune system specifically, accumulating evidence has revealed an immunomodulating effect of green tea/EGCG. Several types of immune cells in both the innate and adaptive immune systems are known to be affected in varying degrees by green tea/EGCG. Among them, the dramatic effect on T cell functions has been repeatedly demonstrated, including T cell activation, proliferation, differentiation, and production of cytokines. In particular, dysregulated T cell function with respect to different subsets of CD4(+) T cells is a critical pathogenic factor in the development of autoimmune inflammatory diseases. Recent studies have shown that EGCG affects the differentiation of naïve CD4(+) T cells into different effector subsets in a way that would be expected to favorably impact autoimmunity. Consistent with these findings, studies using animal models of autoimmune diseases have reported disease improvement in animals treated with green tea/EGCG. Altogether, these studies identify and support the use of EGCG as a potential therapeutic agent in preventing and ameliorating T cell-mediated autoimmune diseases. Given the paucity of information in human studies, the translational value of these findings needs to be verified in future research.

Obesity and aging are both associated with increased inflammation in adipose tissue. In this study, we investigated effect of diet-induced obesity on inflammatory status in young and old mice. Young (2 months) and old (19 months) C57BL/6 mice were fed a low-fat (10%, LF) or high-fat (60%, HF) diet for 4.5 months. Adipose tissue from old/LF mice expressed higher levels of IL-1β, IL-6, TNFα, and cyclooxygenase-2 mRNA compared with young/LF mice. HF diet upregulated expression of all these inflammatory markers in young mice to the levels seen in the aged. Adipocytes, but not stromal vascular cells, from old/LF mice produced more IL-6, TNFα, and prostaglandin (PG)E2 than those from young/LF mice. HF diet resulted in an increase of all these markers produced by adipocytes in young, but only TNFα in old mice. PGE2 produced by peritoneal macrophages (Mϕ's) was upregulated with aging, and HF diet induced more IL-6, TNFα, and PGE2 production in young but not in old mice. Thus, HF diet/obesity induces an inflammatory state in both visceral fat cells and peritoneal Mϕ's of young mice, but not so in old mice. Together, these results suggest that HF diet-induced obesity may speed up the aging process as characterized by inflammatory status. This study also indicates that animals have a differential response, depending on their ages, to HF diet-induced obesity and inflammation. This age-related difference in response to HF diet should be considered when using inflammation status as a marker in investigating adverse health impacts of HF diet and obesity., (Copyright © 2013 International Union of Biochemistry and Molecular Biology, Inc.)

CD4(+) T helper (Th) subsets Th1, Th9, and Th17 cells are implicated in inducing autoimmunity whereas regulatory T cells (Treg) have a protective effect. We and others have previously shown that epigallocatechin-3-gallate (EGCG) attenuates experimental autoimmune encephalomyelitis (EAE) and alters CD4(+) T cell subpopulations. In this study, we investigated how EGCG impacts differentiation of naïve CD4(+) T cells into different effector lineages and report that EGCG impeded Th1, Th9, and Th17 differentiation and prevented IL-6-induced suppression of Treg development. We further showed that EGCG inhibited T-bet, PU.1, and RORγt, the specific transcription factors for Th1, Th9, and Th17 differentiation, respectively. These effects, in turn, may be mediated by EGCG-induced downregulation of transducers p-STAT1 and p-STAT4 for Th1, and p-STAT3 for Th17. EGCG-induced change in Th17/Treg balance may be mediated by its inhibition of IL-6 signaling because EGCG inhibited soluble IL-6R, membrane gp130, and IL-6-induced phosphorylation of STAT3. This notion was further supported by the in vivo results showing inhibited IL-6 and soluble IL-6R but increased soluble gp130 levels in plasma from EAE mice fed EGCG. Together, our results suggest that EGCG modulates development of CD4(+) T cell lineages through impacting their respective and interactive regulatory networks ultimately leading to an attenuated autoimmune response.

One of the proposed health benefits of consuming green tea is its protective effect on autoimmune diseases. Research on the immunopathogenesis of autoimmune diseases has made significant progression in the past few years and several key concepts have been revised. T cells, particularly CD4(+) T helper (Th) cells, play a key role in mediating many aspects of autoimmune diseases. Upon antigenic stimulation, naïve CD4(+) T cells proliferate and differentiate into different effector subsets. Th1 and Th17 cells are the pro-inflammatory subsets of Th cells responsible for inducing autoimmunity whereas regulatory T cells (Treg) have an antagonistic effect. Green tea and its active ingredient, epigallocatechin-3-gallate (EGCG), have been shown to improve symptoms and reduce the pathology in some animal models of autoimmune diseases. Whether or not EGCG's effect is mediated through its impact on Th17 and Treg development has not been studied. We conducted a series of studies to investigate EGCG's effect on CD4(+) T cell proliferation and differentiation as well as its impact on the development of autoimmune disease. We first observed that EGCG inhibited CD4(+) T cell expansion in response to either polyclonal or antigen specific stimulation. We then determined how EGCG affects naïve CD4(+) T cell differentiation and found that it impeded Th1 and Th17 differentiation and prevented IL-6-induced inhibition on Treg development. We further demonstrated that EGCG inhibited Th1 and Th17 differentiation by downregulating their corresponding transcription factors (STAT1 and T-bet for Th1, and STAT3 and RORγt for Th17). These effects provide further explanation for previous findings that administration of EGCG by gavage to experimental autoimmune encephalomyelitis (EAE) mice, an animal model for human multiple sclerosis (MS), reduced the clinical symptoms, brain pathology, and proliferation and TNF-α production of encephalitogenic T cells. Upon further investigating the working mechanisms for EGCG's protective effect in the EAE model, we showed that dietary EGCG dose-dependently attenuated the disease's severity. This protective effect of EGCG is associated with the suppressed proliferation of autoreactive T cells, reduced production of pro-inflammatory cytokines, decreased Th1 and Th17, and increased Treg populations in lymphoid tissues and central nervous system. EGCG-induced shifts in CD4(+) T cell subsets in EAE mice are accompanied by the corresponding changes in their regulator molecules. Recent studies have also highlighted the critical role of Th17/Treg balance in the pathogenesis of rheumatoid arthritis (RA). EGCG has been shown to be anti-inflammatory and protective in several studies using animal models of inflammatory arthritis, but research, at the best, only to start looking into the mechanisms with a focus on T cells. Overall, future research should fully incorporate the current progress in autoimmunity into the study design to expand the power of evaluating EGCG's efficacy in treating autoimmune diseases. Data from human studies are essentially absent and thus are urgently needed., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Aging is associated with declined immune function, particularly T cell-mediated activity, which contributes to increased morbidity and mortality from infectious disease and cancer in the elderly. Studies have shown that nutritional intervention may be a promising approach to reversing impaired immune function and diminished resistance to infection with aging. However, controversy exists concerning every nutritional regimen tested to date. In this article, we will review the progress of research in this field with a focus on nutrition factor information that is relatively abundant in the literature. While vitamin E deficiency is rare, intake above recommended levels can enhance T cell function in aged animals and humans. This effect is believed to contribute toward increased resistance to influenza infection in animals and reduced incidence of upper respiratory infection in the elderly. Zinc deficiency, common in the elderly, is linked to impaired immune function and increased risk for acquiring infection, which can be rectified by zinc supplementation. However, higher than recommended upper limits of zinc may adversely affect immune function. Probiotics are increasingly being recognized as an effective, immune-modulating nutritional factor. However, to be effective, they require an adequate supplementation period; additionally, their effects are strain-specific and among certain strains, a synergistic effect is observed. Increased intake of fish or n-3 PUFA may be beneficial to inflammatory and autoimmune disorders as well as to several age-related diseases. Conversely, the immunosuppressive effect of fish oils on T cell-mediated function has raised concerns regarding their impact on resistance to infection. Caloric restriction (CR) is shown to delay immunosenescence in animals, but this effect needs to be verified in humans. Timing for CR initiation may be important to determine whether CR is effective or even beneficial at all. Recent studies have suggested that CR, which is effective at improving the immune response of unchallenged animals, might compromise the host's defense against pathogenic infection and result in higher morbidity and mortality. The studies published thus far describe a critical role for nutrition in maintaining the immune response of the aged, but they also indicate the need for a more in-depth, wholestic approach to determining the optimal nutritional strategies that would maintain a healthy immune system in the elderly and promote their resistance to infection and other immune-related diseases.

Previously, we demonstrated that in vitro epigallocatechin-3-gallate (EGCG) supplementation inhibited T cell response in mouse spleen cells. In this study, we confirmed this effect of EGCG in mice fed 0.3% EGCG for 6 wk. A coculture with all the combinations of preincubating antigen-presenting cells and T cells with or without EGCG showed that EGCG suppressed antigen-induced T cell proliferation, mainly through a direct effect on T cells. To determine the mechanisms for this effect of EGCG, we stimulated purified mouse T cells with anti-CD3/CD28 in the presence of EGCG (2.5-15 micromol/L) and found that EGCG dose-dependently inhibited cell division and cell cycle progression and this effect of EGCG was more pronounced in CD4(+) than in CD8(+) T cells. Interleukin (IL)-2 concentrations in EGCG-treated cell cultures showed no difference up to 24 h but were higher in the cultures at 48 h compared with the untreated control cells. However, intracellular staining showed no difference between EGCG-treated and untreated control cells in IL-2 synthesis, but EGCG-treated cells expressed less IL-2 receptor (IL-2R) compared with untreated control cells. EGCG did not affect mRNA expression of IL-2 and IL-2R. These results indicate that EGCG-induced IL-2 accumulation in 48 h cultures is due to its reduced utilization. In summary, EGCG directly inhibits T cell proliferative response to both polyclonal and antigen-specific stimulation. CD4(+) cells are more responsive to EGCG than CD8(+) cells. Future studies should determine the effect of EGCG on CD4(+) cell subsets to assess its application in T cell-mediated autoimmune diseases.

alpha-Tocopherol (alpha-Toc) enhances T cell function, whereas little is known in this regard for tocotrienols (T3), the less-known members of the vitamin E family. We pair-fed young (4 mo) and old (23 mo) C57BL/6 mice 0.1% Tocomin 50%, a mixture of T3 and alpha-Toc or a control diet containing an equal amount of alpha-Toc for 6 wk. As expected, lymphocyte proliferation was lower in the old mice compared with the young mice. Lymphocyte proliferation in the old T3 group was significantly higher than that in the old control group, whereas no significant difference was found in young mice. Splenocytes from old mice produced less interleukin (IL)-2, IL-4, IL-6, and IL-10 compared with young mice, whereas no significant age-related difference was found in IL-1beta, tumor necrosis factor-alpha, and interferon-gamma. T3 feeding was associated with a higher IL-1beta production in old mice but not in young mice. Peritoneal macrophages from old mice produced significantly more IL-1beta, IL-6, IL-10, and prostaglandin E(2) (PGE(2)) compared with those from young mice. Mice of both ages fed T3 had higher production of IL-1beta but not PGE(2) or other cytokines. In the in vitro study, splenocytes isolated from young and old mice were supplemented with the purified form of each individual T3 (0.01-10 mumol/L) and mitogen-stimulated cell proliferation was determined. All T3 enhanced lymphocyte proliferation in old but not young mice with a potency order of alpha- > gamma- > delta-T3. Together, these results suggest a beneficial effect of T3 in improving the age-related decline in T cell function.

Ageing is associated with a decline in immune function, which predisposes the elderly to a higher incidence of infections. Information on the mechanism of the age-related increase in susceptibility to Salmonella enterica serovar Typhimurium (S. Typhimurium) is limited. In particular, little is known regarding the involvement of the immune response in this age-related change. We employed streptomycin (Sm)-pretreated C57BL/6 mice to develop a mouse model that would demonstrate age-related differences in susceptibility and immune response to S. Typhimurium. In this model, old mice inoculated orally with doses of 3 x 10(8) or 1 x 10(6) c.f.u. S. Typhimurium had significantly greater S. Typhimurium colonization in the ileum, colon, Peyer's patches, spleen and liver than young mice. Old mice had significantly higher weight loss than young mice on days 1 and 2 post-infection. In response to S. Typhimurium infection, old mice failed to increase ex vivo production of IFN-gamma and TNF-alpha in the spleen and mesenteric lymph node cells to the same degree as observed in young mice; this was associated with their inability to maintain the presence of neutrophils and macrophages at a 'youthful' level. These results indicate that Sm-pretreated C57BL/6 old mice are more susceptible to S. Typhimurium infection than young mice, which might be due to impaired IFN-gamma and TNF-alpha production as well as a corresponding change in the number of neutrophils and macrophages in response to S. Typhimurium infection compared to young mice.

Obesity is a leading risk factor for type 2 diabetes (T2D). Aging is associated with an increase in T2D incidence, which is not totally explained by the much lower prevalence of obesity in the elderly. Low-grade inflammation in adipose tissue (AT) contributes to insulin resistance and T2D. Thus, we determined whether inflammatory responses are up-regulated with age in AT. The results showed that visceral AT from old C57BL mice had significantly higher mRNA expression of the proinflammatory cytokines IL-1beta, IL-6, TNF-alpha, and COX-2 and lower expression of anti-inflammatory PPAR-gamma than those of young mice. We further showed that adipocytes (AD) and not stromal vascular cells including macrophages (Mphi) were the cells responsible for this higher inflammatory state of the aged AT, suggesting that the age-associated increase in AT inflammation is distinguished from that seen in obesity, in which Mphi are the main contributors. However, peritoneal Mphi of either age (young or old) produced more TNF-alpha and IL-6 after incubation in old AD-conditioned medium compared with young AD-conditioned medium. This suggests that in addition to producing more inflammatory cytokines, AD from old mice induce a higher inflammatory response in other cells. Sphingolipid ceramide was higher in old compared with young AD. Reducing ceramide levels or inhibiting NF-kappaB activation decreased cytokine production, whereas the addition of ceramide increased cytokine production in young AD to a level comparable to that seen in old AD, suggesting that ceramide-induced activation of NF-kappaB plays a key role in AT inflammation.

Mushrooms are reported to possess antitumor, antiviral, and antibacterial properties. These effects of mushrooms are suggested to be due to their ability to modulate immune cell functions. However, a majority of these studies evaluated the effect of administering extracts of exotic mushrooms through parental routes, whereas little is known about the immunological effect of a dietary intake of white button mushrooms, which represent 90% of mushrooms consumed in the U.S. In this study, we fed C57BL/6 mice a diet containing 0, 2, or 10% (wt/wt) white button mushroom powder for 10 wk and examined indices of innate and cell-mediated immunity. Mushroom supplementation enhanced natural killer (NK) cell activity, and IFNgamma and tumor necrosis factor-alpha (TNFalpha) production, but only tended to increase IL-2 (P = 0.09) and did not affect IL-10 production by splenocytes. There were significant correlations between NK activity and production of IFNgamma (r = 0.615, P < 0.001) and TNFalpha (r = 0.423, P = 0.032) in splenocytes. Mushroom supplementation did not affect macrophage production of IL-6, TNFalpha, prostaglandin E(2), nitric oxide, and H(2)O(2), nor did it alter the percentage of total T cells, helper T cells (CD4(+)), cytotoxic or suppressive T cells (CD8(+)), regulatory T cells (CD4(+)/CD25(+)), total B cells, macrophages, and NK cells in spleens. These results suggest that increased intake of white button mushrooms may promote innate immunity against tumors and viruses through the enhancement of a key component, NK activity. This effect might be mediated through increased IFNgamma and TNFalpha production.