Noncanonical WNT-5A signaling regulates TGF-β-induced extracellular matrix production by airway smooth muscle cells
Noncanonical WNT-5A signaling regulates TGF-β-induced extracellular matrix production by airway smooth muscle cells
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DOI：
10.1096/fj.12-217539
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发表时间：
2013-04-01
期刊：
影响因子：
4.8
通讯作者：
Gosens, Reinoud
中科院分区：
文献类型：
--
作者：
Kumawat, Kuldeep;Menzen, Mark H.;Gosens, Reinoud
转化生长因子β（TGF-β）是纤维化反应的关键介质，在哮喘中增加，并通过诱导细胞外基质（ECM）蛋白的表达来驱动气道重塑。我们研究了TGF-β诱导气道平滑肌细胞ECM表达的分子机制，并证明了TGF-β和Wingless/整合酶1（WNT）信号转导在ECM沉积中的新联系。气道平滑肌表达丰富的WNT配体，其中非经典WNT-5A表达最深。有趣的是，WNT-5A在从患有哮喘的个体中分离的气道平滑肌细胞中显示出比没有哮喘的个体高2倍的丰度。WNT-5A响应于TGF-β（4 - 16倍; EC 50 0.3 ng/ml）而被显著诱导，并且是气道平滑肌表达胶原蛋白和纤连蛋白所需的。WNT-5A参与非经典WNT信号传导途径，因为抑制Ca 2+和c-Jun N-末端激酶（JNK）信号传导减弱了这种TGF-β反应，而经典WNT拮抗剂Dickkopf 1（DKK-1）则没有。因此，WNT-5A诱导JNK磷酸化和活化的T细胞c1的核因子（NFATc 1）的核转位。此外，WNT-5A受体Frizzled 8（FZD（8））和RYK的沉默减弱了TGF-β诱导的ECM表达。总的来说，这些研究结果表明，非经典WNT-5A信号传导被气道平滑肌细胞TGF-β诱导的ECM产生所激活，这可能在哮喘发病机制中具有重要意义。Kumawat，K.，Menzen，M. H...博斯岛S. T.，Baarsma，H.一、博尔格，P.，Roth，M.，塔姆，M.，Halayko，A. J.，Simoons，M.，普林斯，A.，Postma，D.美国，施密特，M.，和Gosens，R.非经典WNT-5A信号传导调节TGF-β诱导的气道平滑肌细胞细胞外基质产生。FASEB J.27，1631-1643（2013）。www.fasebj.org
Transforming growth factor beta (TGF-beta), a key mediator of fibrotic responses, is increased in asthma and drives airway remodeling by inducing expression of extracellular matrix (ECM) proteins. We investigated the molecular mechanisms underlying TGF-beta-induced ECM expression by airway smooth muscle cells and demonstrate a novel link between TGF-beta and Wingless/integrase 1 (WNT) signaling in ECM deposition. Airway smooth muscle expresses abundant WNT ligands, with the noncanonical WNT-5A being the most profoundly expressed. Interestingly, WNT-5A shows similar to 2-fold higher abundance in airway smooth muscle cells isolated from individuals with asthma than individuals without asthma. WNT-5A is markedly induced in response to TGF-beta (4 -16-fold; EC50 0.3 ng/ml) and is required for collagen and fibronectin expression by airway smooth muscle. WNT-5A engages noncanonical WNT signaling pathways, as inhibition of Ca2+ and c-Jun N-terminal kinase (JNK) signaling attenuated this TGF-beta response, whereas the canonical WNT antagonist Dickkopf 1 (DKK-1) did not. Accordingly, WNT-5A induced JNK phosphorylation and nuclear translocation of nuclear factor of activated T cells c1 (NFATc1). Furthermore, silencing of the WNT-5A receptors Frizzled 8 (FZD(8)) and RYK attenuated TGF-beta-induced ECM expression. Collectively, these findings demonstrate that noncanonical WNT-5A signaling is activated by and necessary for TGF-beta-induced ECM production by airway smooth muscle cells, which could have significance in asthma pathogenesis.-Kumawat, K., Menzen, M. H.., Bos, I. S. T., Baarsma, H. A., Borger, P., Roth, M., Tamm, M., Halayko, A. J., Simoons, M., Prins, A., Postma, D. S., Schmidt, M., and Gosens, R. Noncanonical WNT-5A signaling regulates TGF-beta-induced extracellular matrix production by airway smooth muscle cells. FASEB J. 27, 1631-1643 (2013). www.fasebj.org