Journal
EMBO JOURNAL
Volume 24, Issue 23, Pages 4071-4081Publisher
WILEY
DOI: 10.1038/sj.emboj.7600867
Keywords
PDGF-B; proliferation; TGF-beta; Toll-like receptors; type I interferons
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Funding
- NCI NIH HHS [R01 CA87924, R01 CA087924] Funding Source: Medline
- NIAID NIH HHS [T32 AI060567, R01 AI056154] Funding Source: Medline
- NIGMS NIH HHS [GM07185, T32 GM007185] Funding Source: Medline
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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 TGF beta 1 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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