BMP type II receptor deficiency confers resistance to growth inhibition by TGF-β in pulmonary artery smooth muscle cells: role of proinflammatory cytokines
BMP type II receptor deficiency confers resistance to growth inhibition by TGF-β in pulmonary artery smooth muscle cells: role of proinflammatory cytokines
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DOI：
10.1152/ajplung.00309.2011
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发表时间：
2012-03-01
影响因子：
4.9
通讯作者：
Morrell, Nicholas W.
中科院分区：
文献类型：
--
作者：
Davies, Rachel J.;Holmes, Alan M.;Morrell, Nicholas W.
首页--期刊主要分类--期刊细介绍--期刊题录与文摘--期刊详细文摘内容BMP II型受体缺陷可抵抗转化生长因子-β对肺动脉平滑肌细胞生长的抑制作用：促炎细胞因子的作用。Am J Physiol肺细胞分子Physiol 302：L604-L615,2012。-骨形态发生蛋白II型受体(BMPR-II)的突变是大多数遗传性肺动脉高压和相当一部分零星病例的基础。来自肺动脉高压(PAH)患者的肺动脉平滑肌细胞(PASMCs)不仅表现出BMPs减弱的生长抑制，而且对转化生长因子(TGF)-β1有异常的促有丝分裂反应。我们试图确定在BMPR-II缺陷的PASMCs中，转化生长因子-β1的抗增殖作用丧失的机制。在三种不同的BMPR-II功能障碍模型中，研究了转化生长因子-β1对PASMC增殖的影响：1)HPAH PASMC，2)Bmpr2(-/-)小鼠PASMC，3)对照的人PASMC。BMPR-II的减少始终使人对转化生长因子-β1的生长抑制不敏感。这与典型的转化生长因子-β1/Smad信号的改变无关，而与一种分泌因子有关。微阵列分析显示，对照组和HPAH PASMCs对转化生长因子-β1的转录反应不同，特别是与白细胞介素性和炎症相关的基因。HPAH PASMCs可增强转化生长因子-β1诱导的IL-6和IL-8，该作用可被核因子-kappa B抑制所逆转。此外，IL-6或IL-8的中和抗体可恢复转化生长因子-β1对HPAH PASMCs的抗增殖作用。本研究证实BMPR-II缺乏导致转化生长因子-β1对PASMCs生长抑制失败。这种作用不依赖于Smad，但与不适当地改变了核因子-kappaB信号和增强了IL-6和IL-8的表达有关。我们的研究为测试抗白介素性治疗作为干预措施以中和这种不适当的反应并恢复对转化生长因子-β1的抗增殖反应提供了理论基础。
Davies RJ, Holmes AM, Deighton J, Long L, Yang X, Barker L, Walker C, Budd DC, Upton PD, Morrell NW. BMP type II receptor deficiency confers resistance to growth inhibition by TGF-beta in pulmonary artery smooth muscle cells: role of proinflammatory cytokines. Am J Physiol Lung Cell Mol Physiol 302: L604-L615, 2012. First published January 6, 2012; doi:10.1152/ajplung.00309.2011.-Mutations in the bone morphogenetic protein (BMP) type II receptor (BMPR-II) underlie most cases of heritable pulmonary arterial hypertension (HPAH) and a significant proportion of sporadic cases. Pulmonary artery smooth muscle cells (PASMCs) from patients with pulmonary arterial hypertension (PAH) not only exhibit attenuated growth suppression by BMPs, but an abnormal mitogenic response to transforming growth factor (TGF)-beta 1. We sought to define the mechanism underlying this loss of the antiproliferative effects of TGF-beta 1 in BMPR-II-deficient PASMCs. The effect of TGF-beta 1 on PASMC proliferation was characterized in three different models of BMPR-II dysfunction: 1) HPAH PASMCs, 2) Bmpr2(-/-) mouse PASMCs, and 3) control human PASMCs transfected with BMPR-II small interfering RNA. BMPR-II reduction consistently conferred insensitivity to growth inhibition by TGF-beta 1. This was not associated with altered canonical TGF-beta 1/Smad signaling but was associated with a secreted factor. Microarray analysis revealed that the transcriptional responses to TGF-beta 1 differed between control and HPAH PASMCs, particularly regarding genes associated with interleukins and inflammation. HPAH PASMCs exhibited enhanced IL-6 and IL-8 induction by TGF-beta 1, an effect reversed by NF-kappa B inhibition. Moreover, neutralizing antibodies to IL-6 or IL-8 restored the antiproliferative effect of TGF-beta 1 in HPAH PASMCs. This study establishes that BMPR-II deficiency leads to failed growth suppression by TGF-beta 1 in PASMCs. This effect is Smad-independent but is associated with inappropriately altered NF-kappa B signaling and enhanced induction of IL-6 and IL-8 expression. Our study provides a rationale to test anti-interleukin therapies as an intervention to neutralize this inappropriate response and restore the antiproliferative response to TGF-beta 1.