Nutritional modulation of antitumor immunity.

The composition and quantity of food we eat have a drastic impact on the development and function of immune responses. In this review, we highlight defined nutritional interventions shown to enhance antitumor immunity, including ketogenic, low-protein, high-fructose, and high-fiber diets, as well as dietary restriction. We propose that incorporating such nutritional interventions into immunotherapy protocols has the potential to increase therapeutic responsiveness and long-term tumor control in patients with cancer.

Vitamin A-treated natural killer cells reduce interferon-gamma production and support regulatory T-cell differentiation.

Natural killer (NK) cells are innate cytotoxic lymphocytes that contribute to immune responses against stressed, transformed, or infected cells. NK cell effector functions are regulated by microenvironmental factors, including cytokines, metabolites, and nutrients. Vitamin A is an essential micronutrient that plays an indispensable role in embryogenesis and development, but was also reported to regulate immune responses. However, the role of vitamin A in regulating NK cell functions remains poorly understood. Here, we show that the most prevalent vitamin A metabolite, all-trans retinoic acid (atRA), induces transcriptional and functional changes in NK cells leading to altered metabolism and reduced IFN-γ production in response to a wide range of stimuli. atRA-exposed NK cells display a reduced ability to support dendritic cell (DC) maturation and to eliminate immature DCs. Moreover, they support the polarization and proliferation of regulatory T cells. These results imply that in vitamin A-enriched environments, NK cells can acquire functions that might promote tolerogenic immunity and/or immunosuppression.

Liver sinusoidal endothelial cells orchestrate NK cell recruitment and activation in acute inflammatory liver injury.

Liver sinusoidal endothelial cells (LSECs) rapidly clear lipopolysaccharide (LPS) from the bloodstream and establish intimate contact with immune cells. However, their role in regulating liver inflammation remains poorly understood. We show that LSECs modify their chemokine expression profile driven by LPS or interferon-γ (IFN-γ), resulting in the production of the myeloid- or lymphoid-attracting chemokines CCL2 and CXCL10, respectively, which accumulate in the serum of LPS-challenged animals. Natural killer (NK) cell exposure to LSECs in vitro primes NK cells for higher production of IFN-γ in response to interleukin-12 (IL-12) and IL-18. In livers of LPS-injected mice, NK cells are the major producers of this cytokine. In turn, LSECs require exposure to IFN-γ for CXCL10 expression, and endothelial-specific Cxcl10 gene deletion curtails NK cell accumulation in the inflamed livers. Thus, LSECs respond to both LPS and immune-derived signals and fuel a positive feedback loop of immune cell attraction and activation in the inflamed liver tissue.

Lipid abnormalities in atopic skin are driven by type 2 cytokines.

Lipids in the stratum corneum of atopic dermatitis (AD) patients differ substantially in composition from healthy subjects. We hypothesized that hyperactivated type 2 immune response alters AD skin lipid metabolism. We have analyzed stratum corneum lipids from nonlesional and lesional skin of AD subjects and IL-13 skin-specific Tg mice. We also directly examined the effects of IL-4/IL-13 on human keratinocytes in vitro. Mass spectrometric analysis of lesional stratum corneum from AD subjects and IL-13 Tg mice revealed an increased proportion of short-chain (N-14:0 to N-24:0) NS ceramides, sphingomyelins, and 14:0-22:0 lysophosphatidylcholines (14:0-22:0 LPC) with a simultaneous decline in the proportion of corresponding long-chain species (N-26:0 to N-32:0 sphingolipids and 24:0-30:0 LPC) when compared with healthy controls. An increase in short-chain LPC species was also observed in nonlesional AD skin. Similar changes were observed in IL-4/IL-13-driven responses in Ca2+-differentiated human keratinocytes in vitro, all being blocked by STAT6 silencing with siRNA. RNA sequencing analysis performed on stratum corneum of AD as compared with healthy subjects identified decreased expression of fatty acid elongases ELOVL3 and ELOVL6 that contributed to observed changes in atopic skin lipids. IL-4/IL-13 also inhibited ELOVL3 and ELOVL6 expression in keratinocyte cultures in a STAT6-dependent manner. Downregulation of ELOVL3/ELOVL6 expression in keratinocytes by siRNA decreased the proportion of long-chain fatty acids globally and in sphingolipids. Thus, our data strongly support the pathogenic role of type 2 immune activation in AD skin lipid metabolism.

Expression of IL-22 in the Skin Causes Th2-Biased Immunity, Epidermal Barrier Dysfunction, and Pruritus via Stimulating Epithelial Th2 Cytokines and the GRP Pathway.

Increased expression of Th22 cytokine IL-22 is a characteristic finding in atopic dermatitis (AD). However, the specific role of IL-22 in the pathogenesis of AD in vivo has yet to be elucidated. Consistent with observations in human AD, IL-22 was significantly increased in the AD skin of mice after epicutaneous sensitization to house dust mite allergen. Utilizing a skin-specific inducible transgenic system, we show in the present study that expression of IL-22 in the skin of mice caused an AD-like phenotype characterized by chronic pruritic dermatitis associated with Th2-biased local and systemic immune responses, downregulation of epidermal differentiation complex genes, and enhanced dermatitis upon epicutaneous allergen exposure. IL-22 potently induced the expression of gastrin-releasing peptide (GRP), a neuropeptide pruritogen, in dermal immune cells and sensory afferents and in their skin-innervating sensory neurons. IL-22 also differentially upregulated the expression of GRP receptor (GRPR) on keratinocytes of AD skin. The number of GRP+ cells in the skin correlated with the AD severity and the intensity of pruritus. IL-22 directly upregulated the expression of epithelial-derived type 2 cytokines (thymic stromal lymphopoietin and IL-33) and GRP in primary keratinocytes. Furthermore, GRP not only strongly induced thymic stromal lymphopoietin but it also increased the expression of IL-33 and GRPR synergistically with IL-22. Importantly, we found that the expression of GRP was strikingly increased in the skin of patients with AD. These results indicate that IL-22 plays important pathogenic roles in the initiation and development of AD, in part through inducing keratinocyte production of type 2 cytokines and activation of the GRP/GRPR pathway.

Aspergillus oryzae fermented germinated soybean extract alleviates perimenopausal symptoms in ovariectomised rats.

BACKGROUND: Soybeans have been widely used to alleviate climacteric symptoms. In this study, we investigated the oestrogenic activities of isoflavones extracted from Aspergillus oryzae-challenged germinated soybeans (AO-GS). Eight-week-old virgin Sprague-Dawley female rats were ovariectomised (OVX). The rats were orally administered 0.1 mg kg(-1) 17α-ethinyl oestradiol or three different doses of AO-GS (0.5, 1.0 2.0 g kg(-1) day(-1)) in distilled water for 6 weeks, while control rats were administered vehicle alone. Uterine weights and levels of oestradiol and testosterone in serum were measured. In addition to serum parameters, bone parameters were also acquired by using micro-computed tomography scanning. RESULTS: Treatments of OVX rats with AO-GS changed the secretory profile of serum oestradiol and testosterone. Serum oestradiol levels were significantly increased in OVX rats treated with and AO-GS (0.5, 1.0, 2.0 g kg(-1) day(-1)), while serum testosterone levels were not significantly increased in OVX rats treated with 1.0 g kg(-1) day(-1) of AO-GS. Furthermore, AO-GS (2.0 g kg(-1) day(-1)) significantly attenuated bone loss, increased trabecular bone volume fraction and trabecular thickness, and significantly decreased trabecular pattern factor. CONCLUSION: AO-GS treatments caused moderate oestrogenic activity in OVX rats compared to those treated with oestradiol, suggesting the potential for the use of AO-GS in the treatment of menopausal symptoms and in osteoporosis caused by oestrogen deficiency.

Photoprotective effects of galacto-oligosaccharide and/or Bifidobacterium longum supplementation against skin damage induced by ultraviolet irradiation in hairless mice.

This study aimed at examining whether oral administration of galacto-oligosaccharide (GOS) and Bifidobacterium longum, individually or in combination, could exert photoprotective effects on the skin of hairless mice. GOS and/or Bifidobacterium were administered orally to hairless mice for 12 weeks. Mice were irradiated with UV light daily for four consecutive days. GOS administration increased the water-holding capacity of the skin and prevented transepidermal water loss compared with the control. A reduction in the erythema formation of 16.8% was also observed in the GOS-treated group compared with the control, and CD44 gene expression was significantly increased. Oral administration of GOS or Bifidobacterium significantly increased TIMP-1 and Col1 mRNA expression compared with the control. Our findings support that prebiotics, including GOS, are beneficial not only to the intestine, but also to the skin, and present the possibility of new nutritional strategies for the prevention of UV-induced skin damage.