TLR agonists regulate PDGF-B production and cell proliferation through TGF-beta/type I IFN crosstalk.
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.
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- Up-Regulation
- Transforming Growth Factor beta1
- Transforming Growth Factor beta
- Toll-Like Receptors
- Smad7 Protein
- Smad4 Protein
- Signal Transduction
- Receptors, Immunologic
- RNA, Messenger
- Proto-Oncogene Proteins c-sis
Citation
Published In
DOI
ISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Up-Regulation
- Transforming Growth Factor beta1
- Transforming Growth Factor beta
- Toll-Like Receptors
- Smad7 Protein
- Smad4 Protein
- Signal Transduction
- Receptors, Immunologic
- RNA, Messenger
- Proto-Oncogene Proteins c-sis