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

Abstract

Transforming growth factor‐β (TGF‐β) 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 TGFβ1 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‐β and type I IFNs in determining the specificity of TLR‐mediated gene induction.