Abstract
Transforming growth factor-beta (TGF-beta) and type I interferon (IFN) autocrine/paracrine loops are recognized as key mediators of signaling cascades that control a variety of cellular functions. Here, we describe a novel mechanism by which Toll-like receptor (TLR) agonists utilize these two autocrine/paracrine loops to differentially regulate the induction of PDGF-B, a growth factor implicated in a number of diseases ranging from tumor metastasis to glomerulonephritis. We demonstrate that CpG-specific induction of PDGF-B requires activation of Smads through TGFbeta1 autocrine/paracrine signaling. In contrast, polyinosinic:polycytidylic acid strongly represses CpG's as well as its own intrinsic ability to induce PDGF-B mRNA through type I IFN-mediated induction of Smad7, a negative regulator of Smad3/4. Furthermore, we have shown that this crosstalk mechanism translates into similar regulation of mesangial cell proliferation. Thus, our results demonstrate the importance of crosstalk between TGF-beta and type I IFNs in determining the specificity of TLR-mediated gene induction.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / physiology
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Animals
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Antigens, Differentiation / physiology
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Cell Line
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Cell Proliferation
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Cells, Cultured
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CpG Islands / physiology
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Interferon Type I / physiology*
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Interleukin-1 Receptor-Associated Kinases
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Mesangial Cells / cytology
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Mesangial Cells / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Myeloid Differentiation Factor 88
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NF-kappa B / physiology
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Phosphotransferases (Alcohol Group Acceptor) / physiology
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Poly I-C / metabolism
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Proto-Oncogene Proteins c-sis / biosynthesis*
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RNA, Messenger / metabolism
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Receptors, Immunologic / physiology
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Signal Transduction / physiology*
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Smad4 Protein / metabolism
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Smad7 Protein / physiology
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Toll-Like Receptors / agonists*
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Transforming Growth Factor beta / metabolism
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Transforming Growth Factor beta / physiology*
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Transforming Growth Factor beta1
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Up-Regulation
Substances
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Adaptor Proteins, Signal Transducing
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Antigens, Differentiation
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Interferon Type I
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Myd88 protein, mouse
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Myeloid Differentiation Factor 88
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NF-kappa B
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Proto-Oncogene Proteins c-sis
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RNA, Messenger
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Receptors, Immunologic
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Smad4 Protein
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Smad4 protein, mouse
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Smad7 Protein
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Smad7 protein, mouse
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Tgfb1 protein, mouse
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Toll-Like Receptors
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Transforming Growth Factor beta
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Transforming Growth Factor beta1
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Phosphotransferases (Alcohol Group Acceptor)
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Interleukin-1 Receptor-Associated Kinases
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Irak4 protein, mouse
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Poly I-C