TLR agonists regulate PDGF-B production and cell proliferation through TGF-β/type IIFN crosstalk
TLR agonists regulate PDGF-B production and cell proliferation through TGF-β/type IIFN crosstalk
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DOI：
10.1038/sj.emboj.7600867
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发表时间：
2005-12-07
期刊：
影响因子：
11.4
通讯作者：
Cheng, GH
中科院分区：
文献类型：
--
作者：
Chow, EK;O'Connell, RM;Cheng, GH
转化生长因子-β（TGF-β）和I型干扰素（IFN）自分泌/旁分泌环被认为是控制多种细胞功能的信号级联的关键介质。在这里，我们描述了一种新的机制，Toll样受体（TLR）激动剂利用这两个自分泌/旁分泌环差异调节诱导的PDGF-B，一种生长因子，涉及从肿瘤转移到肾小球肾炎的许多疾病。我们证明，CpG特异性诱导PDGF-B需要通过TGF β 1自分泌/旁分泌信号激活Smads。相反，聚肌苷酸：聚胞苷酸强烈抑制CpG以及其自身的内在能力，通过I型IFN介导的Smad 7诱导PDGF-B mRNA，Smad 3/4的负调节因子。此外，我们已经表明，这种串扰机制转化为肾小球系膜细胞增殖的类似调节。因此，我们的研究结果表明，在确定TLR介导的基因诱导的特异性的TGF-β和I型IFN之间的串扰的重要性。
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.