Activated T cells release bioactive Fas ligand (FasL) in exosomes, which subsequently induce self-apoptosis of T cells. However, their potential effects on cell apoptosis in tumors are still unknown. In this study, we purified exosomes expressing FasL from activated CD8+ T cell from OT-I mice and found that activated T cell exosomes had little effect on apoptosis and proliferation of tumor cells but promoted the invasion of B16 and 3LL cancer cells in vitro via the Fas/FasL pathway. Activated T cell exosomes increased the amount of cellular FLICE inhibitory proteins and subsequently activated the ERK and NF-κB pathways, which subsequently increased MMP9 expression in the B16 murine melanoma cells. In a tumor-invasive model in vivo, we observed that the activated T cell exosomes promoted the migration of B16 tumor cells to lung. Interestingly, pretreatment with FasL mAb significantly reduced the migration of B16 tumor cells to lung. Furthermore, CD8 and FasL double-positive exosomes from tumor mice, but not normal mice, also increased the expression of MMP9 and promoted the invasive ability of B16 murine melanoma and 3LL lung cancer cells. In conclusion, our results indicate that activated T cell exosomes promote melanoma and lung cancer cell metastasis by increasing the expression of MMP9 via Fas signaling, revealing a new mechanism of tumor immune escape.

How the intestinal tract develops a tolerance to foreign antigens is still largely unknown. Here we report that extracellular vesicles (EVs) with TGF-β1-dependent immunosuppressive activity are produced by intestinal epithelial cells (IECs) under physiological conditions. Transfer of these EVs into inflammatory bowel disease (IBD) mice induced by dextran sulfate sodium salt decreases IBD severity by inducing regulatory T cells and immunosuppressive dendritic cells. In contrast, decreased endogenous EV production promotes IBD development. IECs produce EVs with increased levels of TGF-β1 upon IBD development in an ERK-dependent manner. Furthermore, these EVs tend to localize in the intestinal tract associated with epithelial cell adhesion molecule (EpCAM). Knockdown of EpCAM in vivo increases the severity of murine IBD, and the protective effect of EVs from IECs with decreased EpCAM on murine IBD is blunted. Therefore, our study indicates that EVs from IECs participate in maintaining the intestinal tract immune balance.

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We have previously demonstrated that exosomes from dendritic cells (DCs) secreting TGF-β1 (sTGF-β1-EXOs) delay the development of murine inflammatory bowel disease (IBD). In this study, we isolated exosomes from DCs expressing membrane-associated TGF-β1 (mTGF-β1-EXOs) and found mTGF-β1-EXOs had more potent immunosuppressive activity than sTGF-β1-EXOs in vitro. Treatment of mice with mTGF-β1-EXOs inhibited the development and progression of myelin oligodendrocyte glycoprotein (MOG)peptide-induced EAE even after disease onset. Treatment of mice with mTGF-β1-EXOs also impaired Ag-specific Th1 and IL-17 responses, but promoted IL-10 responses ex vivo. Treatment with mTGF-β1-EXOs decreased the frequency of Th17 cells in EAE mice, which might be associated with the down-regulation of the p38, ERK, Stat3, and NF-κB activation and IL-6 expression in DCs. Treatment with mTGF-β1-EXOs maintained the regulatory capacity of Treg cells, and adoptive transfer of CD4 + Foxp3 + Treg cells from mTGF-β1-EXO-treated EAE mice dramatically prevented the development of EAE in the recipients. Moreover, treatment with mTGF-β1-EXOs from C57BL/6 mice effectively prevented and inhibited proteolipid protein (PLP) peptide-induced EAE in BALB/c mice. These results indicate that mTGF-β1-EXOs possess powerful immunosuppressive ability and can effectively inhibit the development and progression of EAE in different strains of mice.Keywords: Autoimmune diseases r Exosomes r TGF-β1 r Th17 r Treg cells IntroductionDCs are unique professional APCs and important for the initiation and regulation of immune response [1,2]. Immature DCs have lower levels of co-stimulatory molecules and usually Correspondence: Dr. Zhijian Cai e-mail: caizj@zju.edu.cn; jlwang@zju.edu.cn induce Ag-specific T-cell anergy [3]. TGF-β1 is a negative regulator of pro-inflammatory immune responses. We previously found that systemic administration of TGF-β1 gene-modified immature DCs delayed the development of dextran sulfate sodiuminduced murine inflammatory bowel disease (IBD) [4]. Therefore, * These authors contributed equally to this work. * * These authors share senior co-authorship.C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 2462 Lei Yu et al. Eur. J. Immunol. 2013. 43: 2461-2472 TGF-β1 may modify DC development toward a regulatory phenotype, inhibiting inflammation. Exosomes, released by almost all types of cells, are small lipid bilayer vesicles with a size of 50-100 nm. They are formed by membrane budding into the lumen of an endocytic compartment, leading to the formation of multivesicular bodies. Fusion of multivesicular bodies to plasma membrane leads to the extracellular release of exosomes [5,6]. Exosomes from DCs transfected with vIL-10, FasL, or IL-4 gene inhibit delayed-type hypersensitivity and collagen-induced murine arthritis [7,8]. These results indicate that exosomes can be effective vehicles to carry immunoregulatory molecules for the treatment of autoimmune diseases.Ag-specific Th1 and Th17 cells are crucial for the development of...

ObjectivesThe present study aimed to investigate the prevalence of central obesity among adults with normal BMI and its association with metabolic diseases in Jilin Province, China.MethodsA population-based cross-sectional study was conducted in 2012 in Jilin Province of China. Information was collected by face to face interview. Descriptive data analysis and 95% confidence intervals (CI) of prevalence/frequency were conducted. Log-binomial regression analyses were used to find the independent factors associated with central obesity and to explore the adjusted association between central obesity and metabolic diseases among adults with normal BMI.ResultsAmong the adult residents with normal BMI in Jilin Province, 55.6% of participants with central obesity self-assessed as normal weight and 27.0% thought their body weight were above normal. 12.7% of central obesity people took methods to lose weight, while 85.3% didn’t. Female, older people and non-manual worker had higher risk to be central obesity among adults with normal BMI. Hypertension, diabetes and hyperlipidemia were significantly associated with central obesity among adults with normal BMI, the PRs were 1.337 (1.224–1.461), 1.323 (1.193–1.456) and 1.261 (1.152–1.381) separately when adjusted for gender, age and BMI.ConclusionsHypertension, diabetes and hyperlipidemia were significantly associated with central obesity among adults with normal BMI in Jilin Province, China. The low rates of awareness and control of central obesity among adults with normal BMI should be improved by government and health department.

The contribution of CE is critical in the diagnosis of GHOO, given the fact that there is a significant difference in the detection rate between CE and MDCT, but there is no significant difference in the rate between CE plus MDCT and CE alone.

These results indicate that remifentanil post-conditioning protects the heart from ischemia-reperfusion injury to a similar extent as of ischemic post-conditioning. This protection involves kappa and delta but not mu opioid receptor activation. This drug has great potential as a clinical post-conditioning modality as it can be given in large doses without prolonged opioid-related side effects.

Celiac disease (CD) is a type of intestinal malabsorption syndrome, in which the patients are intolerant to the gliadin in dietary gluten, resulting in chronic diarrhea and secondary malnutrition. The disease is common in Europe and the United States, but only sporadic reports are found in East Asia including China. Is CD really rare in China? We examined 62 patients by capsule endoscopy for chronic diarrhea from June 2003 to March 2008. Four patients with chronic diarrhea and weight loss were diagnosed to have CD. Under the capsule endoscopy, we observed that the villi of the proximal small bowel became short, and that the mucous membrane became atrophied in these four patients. Duodenal biopsies were performed during gastroscopy and the pathological changes of mucosa were confirmed to be Marsh 3 stage of CD. A gluten free diet significantly improved the conditions of the four patients. We suspect that in China, especially in the northern area where wheat is the main food, CD might not be uncommon, and its under-diagnosis could be caused by its clinical manifestations that could be easily covered by the symptoms from other clinical situations, particularly when it came to subclinical patients without obvious symptom or to patients with extraintestinal symptoms as the initial manifestations.