TLR agonists regulate PDGF-B production and cell proliferation through TGF-beta/type I IFN crosstalk.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Chow, EK; O'connell, RM; Schilling, S; Wang, X-F; Fu, X-Y; Cheng, G

Published Date

  • December 2005

Published In

Volume / Issue

  • 24 / 23

Start / End Page

  • 4071 - 4081

PubMed ID

  • 16308570

Pubmed Central ID

  • 16308570

Electronic International Standard Serial Number (EISSN)

  • 1460-2075

International Standard Serial Number (ISSN)

  • 0261-4189

Digital Object Identifier (DOI)

  • 10.1038/sj.emboj.7600867

Language

  • eng