Abstract
A proliferation-inducing ligand (APRIL), a new TNF family member, supports B-cell survival and tumor cell proliferation. APRIL is secreted as a soluble protein by macrophages, dendritic cells and activated T cells. However, factors involved in regulation of APRIL expression are as yet unknown. In this study, we investigated the effect of TGF-β1 on APRIL expression in P388D1, a mouse macrophage cell line. TGF-β1 induced APRIL mRNA expression in a time- and dose-dependent manner. One nanogram per milliliter of TGF-β1 was optimal and APRIL transcripts appeared as early as 3 h after stimulation. Based on our studies, which included overexpression of Smad3, DN-Smad3, and sh-Smad3, we found that Smad3 mediates APRIL transcription at least partially. Further, experiments using inhibitors revealed that p38MAPK and CREB are also involved in TGF-β1-induced APRIL expression. These results suggest that TGF-β1, through Smad3 and p38MAPK/CREB signaling pathways, stimulates APRIL expression in macrophages.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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B-Lymphocytes / cytology
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B-Lymphocytes / metabolism
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Cell Line
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Cell Proliferation / drug effects*
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Cyclic AMP Response Element-Binding Protein / genetics
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Cyclic AMP Response Element-Binding Protein / metabolism
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Dose-Response Relationship, Drug
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Macrophages / cytology
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Macrophages / drug effects*
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Macrophages / metabolism
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Mice
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Plasmids
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Protein Kinase Inhibitors / pharmacology
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RNA, Messenger / analysis
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RNA, Messenger / biosynthesis
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Signal Transduction / drug effects*
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Signal Transduction / genetics
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Smad3 Protein / genetics
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Smad3 Protein / metabolism
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Transcription, Genetic / drug effects*
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Transfection
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Transforming Growth Factor beta1 / metabolism
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Transforming Growth Factor beta1 / pharmacology*
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Tumor Necrosis Factor Ligand Superfamily Member 13 / genetics
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Tumor Necrosis Factor Ligand Superfamily Member 13 / metabolism*
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
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p38 Mitogen-Activated Protein Kinases / genetics
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p38 Mitogen-Activated Protein Kinases / metabolism*
Substances
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Creb1 protein, mouse
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Cyclic AMP Response Element-Binding Protein
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Protein Kinase Inhibitors
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RNA, Messenger
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Smad3 Protein
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Smad3 protein, mouse
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Tnfsf13 protein, mouse
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Transforming Growth Factor beta1
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Tumor Necrosis Factor Ligand Superfamily Member 13
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p38 Mitogen-Activated Protein Kinases