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In a randomized, double-blind, placebo-controlled trial, 114 patients with birch pollinosis received Lactococcus lactis subsp. cremoris YRC3780 (YRC3780) powder (n = 28, 29, 28, in each dose group) or a placebo (1 g starch powder, n = 29) daily for 12 weeks during the 2016 pollen season. Patients self-recorded their symptom and medication scores daily, and blood samples were evaluated every 4 weeks throughout the treatment observation periods. Symptom and medication scores during the intake period were grouped into 6 consecutive periods of 2 weeks each, and average values were compared between periods. In the YRC3780-treated groups, medication scores were significantly lower than scores in the placebo group during intake periods 3 ( P  < 0.05). In addition, blood levels of thymus- and activation-regulated chemokines (TARC) at 12 weeks were significantly decreased. Consuming at least 10 9 CFU of YRC3780 daily ameliorated the symptoms of birch pollinosis, likely by improving Th1/Th2 balance. [ABSTRACT FROM AUTHOR]

[Display omitted] • L. cremoris YRC3780 acted on various types of immune cells to inhibit IL-4. • L. cremoris YRC3780 regulated Th1/Th2 balance in intestinal DC-T cell coculture. • Oral administration of L. cremoris YRC3780 alleviated symptoms in AD mice. • L. cremoris YRC3780 inhibited IL-4 in Peyer's patch CD4+ T cells of AD mice. Lactococcus lactis subsp. cremoris YRC3780 (L. cremoris YRC3780) was isolated from kefir, and anti-allergic effects have been confirmed in humans. The mechanisms by which L. cremoris YRC3780 affects the Th1/Th2 balance in mice were investigated in vitro , focusing on the intestinal immune response. Simultaneously, a 2,4-dinitrochlorobenzene-induced atopic dermatitis mouse model was used to evaluate the symptom improvement effect of oral administration of L. cremoris YRC3780. The results showed that L. cremoris YRC3780 enhanced IFN-γ and IL-12 production and inhibited IL-4 production from CD4+ T cells in the presence of various types of immune cells. Oral administration of L. cremoris YRC3780 attenuated serum total IgE (p < 0.05) and decreased ear thickness (p < 0.05) in the atopic dermatitis model. The examination of cytokine expression suggested that L. cremoris YRC3780 improved AD-like symptoms by inhibiting IL-4 gene expression from Peyer's patches CD4+ T cells (p < 0.01) and IL-33 gene expression (p < 0.05) in the draining lymph nodes. [ABSTRACT FROM AUTHOR]

Abstract: Peyer''s patches (PPs) are potential sites where specific mucosal immune responses and oral tolerance are induced. The unique features of these immune responses are thought to occur in micromilieu and are largely affected by antigen-presenting cells (APCs) such as dendritic cells. In this study, we investigated the cytokine profiles induced by the activation of CD4+ T cells of PPs. PP cells from TCR transgenic mice secreted greater amounts of IL-5 and IL-6 than spleen cells after antigenic stimulation. IL-5 was mainly produced by PP non-T cells, whereas IL-6 was secreted by PP CD4+ cells. PPs contained two major populations including naïve and memory/activated CD4+ cells; both populations secreted IL-6 upon activation. We also found that CD4+/CD62Lhi naïve cells from PPs secreted a greater amount of IL-6 after stimulation than those from the spleen. Furthermore, subtraction and qPCR analyses revealed that PP CD4+/CD62Lhi cells express a greater amount of transcripts of GA-binding protein β subunit 1 than those of the spleen. These results suggest that naïve T cells as well as non-T cells and activated/memory T cells from PPs are distinct from their splenic counterparts and thus cause unique immune responses the in intestine. [Copyright &y& Elsevier]

FoSHU (food for specified health uses) are evidence-based functional foods regulated and approved by the Japanese government. Products to improve intestinal microflora were developed using probiotics/prebiotics and were approved as FoSHU to promote gut health. Food substances which suppress intestinal digestive enzymes were also used to develop FoSHU products to lower blood glucose or lipid levels. Recent studies have shown that dietary components, particularly probiotics/prebiotics, may play important roles in regulating the gut immune system. Although scientific evidence is still lacking, they may suppress intestinal inflammation and allergic reactions and therefore may hold promise as ingredients in functional foods. [ABSTRACT FROM AUTHOR]

Background: Clarification of the mechanisms underlying the development of food-sensitive intestinal inflammation will provide an important clue to combating food allergies. Objective: To establish a model of intestinal inflammation caused by oral administration of antigen without additional treatments, we focused on the ovalbumin (OVA) 23-3 T-cell receptor transgenic mouse, which had been reported to have high serum antigen-specific IgE responses to the feeding of an egg white diet. Methods: Changes in body weight of mice fed an egg white diet were monitored throughout the 28-day experimental period. After the 28-day feeding, intestinal tissues were harvested for histologic examination. Endogenous production of cytokines and histamine in the jejunum, and production of cytokines secreted by OVA-specific CD4+ T cells purified from mesenteric lymph nodes, were analyzed. Results: Egg white diet–fed OVA23-3 mice developed weight loss and inflammation with villous atrophy and goblet cell hyperplasia, especially in the jejunum. A further characteristic feature was evidence of weight recovery and tissue repair. Jejunal inflammation was also observed in egg white diet–fed recombination activating gene (RAG)-2–deficient OVA23-3 mice. In addition, tissue sections revealed significant infiltration of specific IgE-positive cells and IgE-positive degranulating mast cells. Higher levels of IL-4 and significant levels of histamine were detected in the tissues. In the supernatant of OVA-stimulated T cells, IL-10 levels were also markedly elevated. Conclusion: We report that high-dose and continuous intake of primitive OVA alone induces enteropathy containing regions under repair in OVA23-3 mice. Antigen-specific T cells and inflammatory cells primed by TH2 responses play important roles in regulation of development and improvement of the disease. Clinical implications: Long-term antigen intake causes TH2-dependent and food-sensitive enteropathy followed by tissue repair. [Copyright &y& Elsevier]

The oral administration of antigen can lead to systemic antigen-specific hyporesponsiveness, also known as oral tolerance. This phenomenon is a representative form of immune tolerance to exogenous antigen under physiological conditions. We have previously reported that long term feeding of dietary antigen to ovalbumin-specific T cell receptor (TCR) transgenic mice induced oral tolerance of peripheral T ceils with impairment in their TCR-induced calcium-signaling pathway. In this study, we utilized two-dimensional electrophoresis to compare intracellular protein expression patterns of orally tolerant and unsensitized CD4 T cells. We detected 26 increased and 16 decreased protein spots and identified 35 of these by mass spectrometry. The results indicated that the expression of caspases was up-regulated and that the protein levels of intact proteins susceptible to caspase cleavage, such as Grb2-related adaptor downstream of Shc (GADS), were decreased in orally tolerant CD4 T cells. Western blotting experiments confirmed that expression of the active form of caspase-3 and the antiapoptotic factor, X-linked inhibitor of apoptosis, were both up-regulated in orally tolerant CD4 T cells, which were found to be nonapoptotic. We further demonstrated that orally tolerant CD4 T cells could not form normal TCR signaling complexes associated with GADS and showed down-regulated phospholipase C-γ1 activation, which is likely to contribute to the impairment of TCR-induced calcium signaling. Our findings indicate that orally tolerant CD4 T cells up-regulate caspase activation and show decreased levels of caspase-targeted proteins, including TCR signaling-associated molecules, while up-regulating antiapoptotic factors, all of which appear to contribute to their unique tolerant characteristics. [ABSTRACT FROM AUTHOR]

• Goldenberry pomace and seed oils (GPO/GSO) contained > 85% unsaturated fatty acids. • Linoleic was the major fatty acid, and trilinolein was the dominant TAG in GPO & GSO. • In DSC, the most significant peaks occurred at low temperatures for GPO and GSO. • FTIR spectra showed that GPO and GSO did not contain peroxides or trans fatty acids. The chemical and thermal characteristics of goldenberry pomace oil (GPO) and goldenberry seed oil (GSO) were investigated. GPO and GSO contained high levels of unsaturated fatty acids (90.1% and 85.1%, respectively), and the major fatty acid was linoleic (62.0% and 72.8%, respectively). Additionally, GPO contained eleven triacylglycerol (TAG) species, three of which represented 82.7%, namely C54:6, C54:4 and C52:4, and trilinolein was the dominant one (35.5%). GSO contained nine TAG species, two of which represented 80.3%, namely C54:6 and C52:4, and trilinolein was dominant (53.3%). The DSC analysis of GPO and GSO revealed that three exothermal peaks were detected during cooling. Three endothermal peaks (one of which is exothermal for GSO) were detected during melting, and the most significant peaks occurred at low temperatures. FTIR spectra indicated that GPO and GSO did not contain peroxides or trans fatty acids, but they did contain low concentrations of free fatty acids. [ABSTRACT FROM AUTHOR]

The destiny and activity of sterol regulatory element-binding proteins (SREBPs) in the nucleus are regulated by modification with ubiquitin, small ubiquitin-like modifier (SUMO), or phosphorus. ERK-dependent phosphorylation causes an increase in their transcriptional activity, whereas SUMO modification halts it. We hypothesized a causal linkage between phosphorylation and sumoylation because their sites are very closely located in SREBP-1 and -2 molecules. When Ser455, a phosphorylation site in SREBP-2, was substituted with Ala, this SREBP-2 mutant was more efficiently modified by SUMO-1. On the other hand, substitution of Asp inhibited SUMO conjugation, mimicking phosphoserine. When cells were cultured with insulin-like growth factor-i, sumoylation of SREBP-2 was decreased with an increase in its phosphorylation, but SREBP-2(S455A) was continuously sumoylated. An ERK cascade inhibitor, U0126, inversely augmented SUMO modification of SREBP-2. Insulin-like growth factor-1 treatment stimulated the expression of SREBP target genes such as the low density lipoprotein (LDL) receptor, squalene synthase, and hydroxymethylglutaryl-CoA synthase genes. These results indicate that growth factor-induced phosphorylation of SREBP-2 inhibits sumoylation, thereby facilitating SREBP transcriptional activity. Glutathione S-transferase pulldown assays revealed that wild-type SREBP-2, but not a mutant lacking Lys464, interacts with HDAC3 preferentially among the histone deacetylase family members. HDAC3 small interfering RNA induced gene expression of the LDL receptor and thereby augmented fluorescently labeled LDL uptake in HepG2 cells. In summary, growth factors inhibit sumoylation of SREBPs through their phosphorylation, thus avoiding the recruitment of an HDAC3 corepressor complex and stimulating the lipid uptake and synthesis required for cell growth. [ABSTRACT FROM AUTHOR]

β-Glucan refers to a heterogeneous group of chemically defined storage polysaccharides containing β-(1,3)- d -linked glucose polymers with branches connected by either β-(1,4) or β-(1,6) glycosidic linkage. To date, an extensive amount of scientific evidence supports their multifunctional biological activities, but their potential involvement in the progression of premalignant lesions remains to be clarified. A4gnt KO mice that lack α1,4- N -acetylglucosamine-capped O -glycans in gastric gland mucin are a unique animal model for gastric cancer because the mutant mice spontaneously develop gastric cancer through hyperplasia-dysplasia-adenocarcinoma sequence. In particular, A4gnt KO mice show gastric dysplasia during 10–20 weeks of age. Here we investigated the putative gastro-protective activity of brown seaweed-derived β-glucan (Laminaran) against development of gastric dysplasia, precancerous lesion for gastric cancer in A4gnt KO mice. The mutant mice at 12 weeks of age were randomly assigned into three treatment groups namely, wildtype control + distilled water (normal control), A4gnt KO mice + distilled water (untreated control), and A4gnt KO mice + 100 mg/kg Laminaran. After 3 weeks, the stomach was removed and examined for morphology and gene expression patterns. In contrast to the untreated control group, administration of Laminaran substantially attenuated gastric dysplasia development and counterbalanced the increased induction in cell proliferation and angiogenesis. Furthermore, Laminaran treatment effectively overcame the A4gnt KO-induced alteration in the gene expression profile of selected cytokines as revealed by real-time PCR analysis. Collectively, our present findings indicate that β-glucan can potentially restrain the development of gastric dysplasia to mediate their tissue-preserving activity. [ABSTRACT FROM AUTHOR]

To examine novel functions of milk basic protein (MBP) in T-cell-related inflammatory diseases, such as autoimmune diseases and allergies, we evaluated the effects of MBP on the causative responses of ovalbumin (OVA)-specific T cells in a food-allergic enteropathy model, OVA23-3 mice, which express an OVA-specific T-cell receptor gene. The OVA-specific CD4+ T cells of the mesenteric lymph nodes (MLN) from OVA23-3 mice were cultured with CD11c+ dendritic cells of MLN from BALB/cA mice in the absence or presence of MBP following stimulation with OVA; then the levels of CD69 expression and the levels of cytokine production by CD4+ T cells were measured to evaluate activation. The effects of MBP supplementation of OVA 23-3 mice were assessed by feeding a diet containing OVA (OVA diet) with or without MBP for 28 d. Intestinal inflammation, together with activation and cytokine production of CD4+ T cells by MLN, as well as femoral bone mineral density, were measured. In in vitro culture, MBP inhibited excess activation and IL-4 production by CD4+ T cells. The supplementation of MBP to the OVA diet attenuated OVA-specific IgE production in OVA-diet-fed OVA23-3 mice and slightly resolved developing enteropathy caused by excess IL-4 production by CD4+ T cells. Feeding OVA diet to OVA23-3 mice exhibited bone loss accompanied with enteropathy, whereas MBP supplementation prevented bone loss and increased osteoprotegerin, an osteoclastogenesis inhibitory factor, in the mice. The inhibition of T-cell-activation in both MLN and bone marrow by MBP supplementation may help prevent increased IgE levels caused by excessive IL-4 production and bone loss accompanied by enteropathy. Our findings show that MBP may help attenuate both T-cell-related inflammation and bone loss. [ABSTRACT FROM AUTHOR]

Abstract: It has been demonstrated that intestinal commensal bacteria induce immunoglobulin (Ig) A production by promoting the development of gut-associated lymphoid tissues in the small intestine. However, the precise mechanism whereby these bacteria modulate IgA production in the large intestine, which harbors the majority of intestinal commensals, is poorly understood. In addition, it is not known which commensal bacteria induce IgA production in the small intestine and which induce production in the large intestine. To address these issues, we generated gnotobiotic mice mono-associated with different murine commensal bacteria by inoculating germ-free (GF) mice with Lactobacillus johnsonii or Bacteroides acidifaciens. In GF mice, IgA production was barely detectable in the small intestine and was not detected in the large intestine. Interestingly, total IgA secretion in the large intestinal mucosa of B. acidifaciens mono-associated (BA) mice was significantly greater than that of GF and L. johnsonii mono-associated (LJ) mice. However, there was no difference in total IgA production in the small intestine of GF, LJ and BA mice. In addition, in the large intestine of BA mice, the expression of IgA+ cells and germinal center formation were more remarkable than in GF and LJ mice. Furthermore, B. acidifaciens-specific IgA was detected in the large intestine of BA mice. These results suggest that the production of IgA in the large intestine may be modulated by a different mechanism than that in the small intestine, and that B. acidifaciens is one of the predominant bacteria responsible for promoting IgA production in the large intestine. [Copyright &y& Elsevier]

Abstract: Colonization of the gut by commensal bacteria modulates the induction of oral tolerance and allergy. However, how these intestinal bacteria modulate antigen-specific T cell responses induced by oral antigens remains unclear. In order to investigate this, we used germ-free (GF) ovalbumin (OVA)-specific T cell receptor transgenic (OVA23-3) mice. Conventional (CV) or GF mice were administered an OVA-containing diet. Cytokine production by CD4+ cells from spleen (SP), mesenteric lymph nodes (MLN) and Peyer''s patches (PP) was evaluated by ELISA, as was the peripheral antibody titer. T cell phenotype was assessed by flow cytometry. CD4+ cells from the SP and MLN of CV and GF mice fed an OVA diet for 3 weeks produced significantly less IL-2 than the corresponding cells from mice receiving a control diet, suggesting that oral tolerance could be induced at the T cell level in the systemic and intestinal immune systems of both bacterial condition of mice. However, we also observed that the T cell hyporesponsiveness induced by dietary antigen was delayed in the systemic immune tissues and was weaker in the intestinal immune tissues of the GF mice. Intestinal MLN and PP CD4+ T cells from these animals also produced lower levels of IL-10, had less activated/memory type CD45RBlow cells, and expressed lower levels of CTLA-4 but not Foxp3 compared to their CV counterparts. Furthermore, GF mice produced higher serum levels of OVA-specific antibodies than CV animals. CD40L expression by SP CD4+ cells from GF mice fed OVA was higher than that of CV mice. These results suggest that intestinal commensal bacteria promote T cell hyporesponsiveness and down-regulate serum antibody responses induced by dietary antigens through modulation of the intestinal and systemic T cell phenotype. [Copyright &y& Elsevier]

Abstract: Oral tolerance is a key feature of intestinal immunity, generating systemic tolerance to ingested antigens (Ag). Dendritic cells (DC) have been revealed as important immune regulators, however, the precise role of DC in oral tolerance induction remains unclear. We investigated the characteristics of DC in spleen, mesenteric lymph node (MLN), and Peyer''s patch (PP) after oral Ag administration in a TCR-transgenic mouse model. DC from PP and MLN of tolerized mice induced IL-10 production but not Foxp3 expression in cocultured T cells. IL-10 production was markedly increased after 5–7-day Ag administration especially in PP DC. On the other hand, IL-27 production was increased after 2–5-day Ag administration. CD11b+ DC, which increased after ingestion of Ag, prominently expressed IL-10 and IL-27 compared with CD11b− DC. These results suggest that IL-10 and IL-27 producing DC are increased by interaction with antigen specific T cells in PP, and these DC act as an inducer of IL-10 producing T cells in oral tolerance. [Copyright &y& Elsevier]

Abstract: Bifidobacterium is a dominant bacterial species among commensals in the human intestine and is thought to have probiotic immunomodulatory effects. In this study, we investigated the effect of the association with Bifidobacterium pseudocatenulatum JCM 7041 (Bp) on dietary ovalbumin (OVA)-specific immune responses using germ-free OVA-specific T cell receptor transgenic mice (OVA23-3 mice). We established germ-free OVA23-3 mice, and then associated with Bp (BIF group) or without (CONT group) and additionally associated with segmented filamentous bacteria (SFB) and clostridia in both groups. BIF and CONT mice were fed an egg-white diet containing OVA for 1 week. Cytokine production in response to OVA by cells of Peyer''s patches (PPs) and lamina propria (LP) from the small and large intestine was measured. Interferon (IFN)-γ and interleukin (IL)-6 production by PP cells from BIF group mice was lower than that of the CONT group. The proportion of PP cells expressing CD4+CD62Llow, an activated/memory T cell phenotype, was higher in BIF group mice than the CONT group. Furthermore, LP cells from the small intestine in Bp-associated mice showed a tendency to produce slightly lower IFN-γ and IL-6, while the cells from large intestine produced markedly higher IFN-γ, IL-5 and IL-6 than those in the CONT group. The pattern of cytokine production by PP in BIF animals was similar to those isolated from conventional mice. These results suggest that intestinal association with Bp might down-regulate excessive immune responses to dietary antigens of the small intestine but enhance those of the large intestine. [Copyright &y& Elsevier]

Abstract: Beneficial effects of lactobacilli have been reported for patients with allergic diseases and intestinal disorders such as inflammatory bowel disease. However, it is not fully understood how such bacteria influence the immunologic response. For this purpose, we investigated the effect of Lactobacillus acidophilus strain L-92 (L-92) on antigen-stimulated T cell responses in vitro and in vivo. In vitro, L-92 decreased the proliferation of CD4+ T cells stimulated with antigen, and also induced apoptosis of antigen-stimulated T cells. On the other hand, interferon (IFN)-γ secretion from naïve T cells was increased while interleukin (IL)-4 secretion was decreased by L-92. Co-culture with L-92 induced apoptosis of differentiated Th1 and Th2 cells. The degree of apoptosis induction was higher in Th2 cells. Moreover, L-92 up-regulated the expression of B7-H1 and down-regulated that of B7-H2 on dendritic cells (DCs), and DCs exposed to L-92 also induced apoptosis of antigen-stimulated T cells. Finally, orally administered L-92 induced apoptosis of OVA-specific TCR Tg T cells. These results indicate that L-92 attenuates the CD4+ T cell response by inducing DC-mediated apoptosis and that it might exert beneficial effects in patients with diseases resulting from a hyper-response of CD4+ T cells. [Copyright &y& Elsevier]

In previous studies it was demonstrated that sterol regulatory element-binding proteins (SREBPs) are able to interact with one of the nuclear receptors, hepatocyte nuclear receptor (HNF)-4, and that this interaction regulates transcriptional activities of these proteins (Misawa, K., Horiba, T., Arimura, N., Hirano, Y., Inoue, J., Emoto, N., Shimano, H., Shimizu, M., and Sato, R. (2003) 1. Biol. Chem. 278, 36176-36182; Yamamoto, T., Shimano, H., Nakagawa, Y., Ide, T., Yahagi, N., Matsuzaka, T., Nakakuki, M., Takahashi, A., Suzuki, H., Sone, H., Toyoshima, H., Sato, R., and Yamada, N. (2004) J. Biol. Chem. 279, 12027- 12035). In an attempt to identify other nuclear receptor family members affecting the SREBP transcriptional activities, we found that the liver receptor homolog (LRH)-1 suppresses them. Several types of luciferase assays revealed that coexpression of these two proteins (LRH-1 and SREBP-1a, -1c, or -2) results in reciprocal inhibition of the transcriptional activity of each protein. It was confirmed that suppression in endogenous LRH-1 by small interference RNA stimulates the mRNA levels of certain SREBP target genes and that elevation in active SREBPs in the nucleus in response to cholesterol depletion suppresses the LRH-1 activity. In vitro/in vivo glutathione S-transferase pulldown experiments demonstrated that the basic helix-loop-helix-leucine zipper domain in SREBP-2 binds to the ligand- binding domain in LRH-1. Furthermore, we found that SREBP-2 interferes with the recruitment of a coactivator of LRH-1, the peroxisome proliferator-activated receptor γ coactivator-1α, thereby leading to the inhibition of the LRH-1 transcriptional activity. These results clearly indicate that the interaction between SREBPs and LRH-1 exerts a suppressive influence on their target gene expression responsible for cholesterol and bile acid metabolism. [ABSTRACT FROM AUTHOR]

Abstract: Intraepithelial lymphocytes (IELs) are considered to drive immune surveillance of the epithelial layer to the mucosa, which is initially exposed to exogenous antigens. However, how IELs are activated by orally administered antigens remains unclear. To clarify this mechanism, we fed ovalbumin (OVA) to T cell receptor transgenic (TCR-Tg) mice with OVA-specific MHC class II-restricted TCR and found that the cytotoxic activity of IELs was increased against both NK and LAK target cells, but notably reduced after depleting CD8+ IELs. Cytoplasmic staining showed that the production of IFN-γ and IL-2 was increased in mice fed with OVA both in the supernatant of cultured IELs with immobilized anti-CD3mAb and in fresh CD4+ IELs. In contrast, the cytotoxic activity against NK and LAK target cells and the production of IL-2 and IFN-γ was decreased in splenic T cells from mice fed with OVA. However, when the splenic T cells from these mice were cultured with OVA and IL-2, IFN-γ production recovered. The decreased response demonstrated the clonal anergy of T cells. Furthermore, tumor growth was enhanced in TCR-Tg mice carrying an OVA-transfected counterpart A20 B cell lymphoma (OVA-A20) and fed with OVA. These results indicate that the oral administration of soluble antigens can activate CD4+ IELs in an antigen-specific manner but induces hyporesponsiveness in the spleen. In addition, Th1-type cytokines produced by activated CD4+ IEL might provide a bystander effect on the cytotoxic activity of IELs. [Copyright &y& Elsevier]

A T-cell receptor (TCR) antagonist is an analog of a peptide ligand for TCR that inhibits T-cell responses to the original peptide. We investigated the effects of a TCR antagonist on cytokine secretion of naive CD4+ T cells and their differentiation into type-1 and type-2 helper T cells (Th1 and Th2) induced by stimulation with varying doses of an antigenic peptide. In the presence of a TCR antagonist peptide, proliferation of naive CD4+ T cells and antigen dose-dependent secretion of interferon-γ, a typical Th1-type cytokine, by these cells was down-regulated. With respect to the secretion of interleukin-4 (IL-4), a typical Th2-type cytokine, the TCR antagonist raised the concentration of the antigenic peptide required to elicit maximal IL-4 production and, surprisingly, significantly increased the maximum level of IL-4 secretion. Similar effects induced by the TCR antagonist were observed on the Th1/Th2 differentiation of naive CD4+ T cells. These results clearly indicate that, for naive CD4+ T cells, a TCR antagonist has the potential to change the balance of Th1/Th2 cytokine secretion and even enhance Th2 responses. [Copyright &y& Elsevier]

Intraepithelial lymphocytes (IELs) play important roles in intestinal mucosal immunity. Although fatty acids are known to modulate the functions of immune effector cells, there has been no information about how fat exposure affects immunological function of IELs. In this study, we examined how fatty acids of various chain lengths modulate the production of interferon (IFN)-γ by IELs stimulated with T-cell receptor (TCR) or interleukin (IL)-12/IL-18. IELs isolated from the small intestine of BALB/c mice were stimulated with plate-coated anti-CD3 monoclonal antibody (mAb) or IL-12/IL-18. They were coincubated in microtiter plates for 3 days with various concentrations of fatty acid micelles. We used arachidonic acid, linoleic acid, and oleic acid as long-chain fatty acids, and used octanoic acid as a medium-chain fatty acid. IFN-γ in the supernatants were measured by ELISA, and the expression of IFN-γ mRNA in IELs was determined by RT-PCR. Significant production of IFN-γ from IELs was observed after anti-CD3 mAb stimulation. The combination of IL-12 and IL-18 induced significant levels of IFN-γ production without TCR stimulation. Increased IFN-γ mRNA was also observed after anti-CD3 or IL-12/IL-18 stimulation. Long-chain fatty acids dose-dependently inhibited the stimulated-IFN-γ production at concentrations greater than 10 μM, but the medium-chain fatty acid did not cause any significant changes in IFN-γ production. IFN-γ production from γδ IELs was very low compared with αβ IELs, however, both populations showed similar attenuating patterns when treated with long-chain fatty acids. There is a possibility that the exposure of IELs to intraluminal fatty acids significantly modifies the immune function of intestinal mucosa. [Copyright &y& Elsevier]