Abstract
During infection, TLR agonists are released and trigger mature as well as differentiating innate immune cells. Early encounter with TLR agonists (R848; LPS) blocks conventional differentiation of CD14(+) monocytes into immature dendritic cells (iDCs) resulting in a deviated phenotype. We and others characterized these APCs (TLR-APC) by a retained expression of CD14 and a lack of CD1a. Here, we show in addition, expression of programmed death ligand-1 (PD-L1). TLR-APCs failed to induce T-cell proliferation and furthermore were able to induce CD25(+) Foxp3(+) T regulatory cells (Tregs). Since PD-L1 is described as a key negative regulator and inducer of tolerance, we further analyzed its regulation. PD-L1 expression was regulated in a MAPK/cytokine/STAT-3-dependent manner: high levels of IL-6 and IL-10 that signal via STAT-3 were produced by TLR-APCs. Blocking of STAT-3 activation prevented PD-L1 expression. Moreover, chromatin immunoprecipitation revealed direct binding of STAT-3 to the PD-L1 promoter. Those findings indicate a pivotal role of STAT-3 in regulating PD-L1 expression. MAPKs were indirectly engaged, as blocking of p38 and p44/42 MAPKs decreased IL-6 and IL-10 thus reducing STAT-3 activation and subsequent PD-L1 expression. Hence, during DC differentiation TLR agonists induce a STAT-3-mediated expression of PD-L1 and favor the development of tolerogenic APCs.
Copyright © 2011 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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Antigen-Presenting Cells / cytology
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Antigen-Presenting Cells / drug effects
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Antigen-Presenting Cells / immunology*
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Antigen-Presenting Cells / metabolism*
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Antigens, CD / metabolism*
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Antigens, CD1 / metabolism
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B7-H1 Antigen
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Cell Differentiation / drug effects
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Cell Differentiation / immunology
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Dendritic Cells / cytology
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Dendritic Cells / immunology
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Gene Expression Regulation / immunology*
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Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology
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Histocompatibility Antigens Class II / metabolism
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Humans
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Imidazoles / pharmacology
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Immune Tolerance / physiology*
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Interleukin-10 / metabolism
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Interleukin-4 / pharmacology
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Interleukin-6 / metabolism
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Lipopolysaccharide Receptors / metabolism
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Lymphocyte Culture Test, Mixed
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Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 3 / metabolism
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Monocytes / cytology
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Monocytes / drug effects
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Monocytes / immunology
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Phosphorylation / drug effects
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Protein Kinase Inhibitors / pharmacology
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STAT Transcription Factors / antagonists & inhibitors
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STAT Transcription Factors / metabolism
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STAT3 Transcription Factor / antagonists & inhibitors
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STAT3 Transcription Factor / metabolism*
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Signal Transduction / immunology*
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T-Lymphocyte Subsets / immunology
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T-Lymphocytes, Regulatory / immunology
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Toll-Like Receptors / agonists
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Antigens, CD
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Antigens, CD1
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B7-H1 Antigen
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CD1a antigen
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CD274 protein, human
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Histocompatibility Antigens Class II
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IL10 protein, human
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IL6 protein, human
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Imidazoles
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Interleukin-6
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Lipopolysaccharide Receptors
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Protein Kinase Inhibitors
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STAT Transcription Factors
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STAT3 Transcription Factor
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STAT3 protein, human
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Toll-Like Receptors
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Interleukin-10
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Interleukin-4
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Granulocyte-Macrophage Colony-Stimulating Factor
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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p38 Mitogen-Activated Protein Kinases
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resiquimod