Abstract
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; Exosomes; TGF-β1; Th17; Treg cells.
© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adoptive Transfer
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Animals
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Autoimmunity / immunology
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Cell Proliferation
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Cells, Cultured
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Dendritic Cells / immunology
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Dendritic Cells / metabolism
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Encephalomyelitis, Autoimmune, Experimental / immunology*
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Encephalomyelitis, Autoimmune, Experimental / prevention & control
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Enzyme Activation
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Exosomes / immunology*
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Exosomes / metabolism
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Extracellular Signal-Regulated MAP Kinases / biosynthesis
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Female
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Green Fluorescent Proteins / genetics
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Immunosuppression Therapy
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Inflammatory Bowel Diseases / immunology
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Interleukin-10 / metabolism
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Interleukin-17 / metabolism
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Interleukin-6 / biosynthesis
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Lymphocyte Activation / immunology
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Myelin-Oligodendrocyte Glycoprotein / metabolism
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NF-kappa B / biosynthesis
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NF-kappa B / metabolism
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STAT3 Transcription Factor / biosynthesis
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STAT3 Transcription Factor / metabolism
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T-Lymphocytes, Regulatory / immunology*
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T-Lymphocytes, Regulatory / metabolism
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Th1 Cells / immunology
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Th1 Cells / metabolism
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Th17 Cells / immunology
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Th17 Cells / metabolism
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Transforming Growth Factor beta1 / immunology*
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Transforming Growth Factor beta1 / metabolism
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p38 Mitogen-Activated Protein Kinases / biosynthesis
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Interleukin-17
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Interleukin-6
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Mog protein, mouse
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Myelin-Oligodendrocyte Glycoprotein
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NF-kappa B
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STAT3 Transcription Factor
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Stat3 protein, mouse
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Transforming Growth Factor beta1
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Interleukin-10
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Green Fluorescent Proteins
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Extracellular Signal-Regulated MAP Kinases
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p38 Mitogen-Activated Protein Kinases