Simultaneous Transforming Growth Factor β-Tumor Necrosis Factor Activation and Cross-talk Cause Aberrant Remodeling Response and Myocardial Fibrosis in Timp3-deficient Heart
Simultaneous Transforming Growth Factor β-Tumor Necrosis Factor Activation and Cross-talk Cause Aberrant Remodeling Response and Myocardial Fibrosis in Timp3-deficient Heart
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DOI：
10.1074/jbc.m109.028449
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发表时间：
2009-10-23
影响因子：
4.8
通讯作者：
Khokha, Rama
中科院分区：
文献类型：
--
作者：
Kassiri, Zamaneh;Defamie, Virginie;Khokha, Rama
多效性细胞因子、转化生长因子 β 1 (TGF β 1) 和肿瘤坏死因子 (TNF) 在响应损伤的组织稳态中发挥着关键作用，并与多种人类疾病和癌症有关。我们报道了 Timp3（金属蛋白酶 3 的组织抑制剂）的缺失会导致 TNF 信号传导和心血管功能异常。在这里，我们发现 Timp3(-/-) 小鼠中 TGF β 1 和 TNF 信号传导的并行失调会放大它们在心脏对机械应力（压力超负荷）反应开始时的串扰，从而导致纤维化和早期心力衰竭。微阵列分析显示 Timp3(-/-) 心脏中具有独特的基因表达谱，强调 TGF beta 1 信号传导的激活是纤维化的潜在机制。建立新生儿心肌细胞-心脏成纤维细胞共培养物以测量已知在体内机械应力后诱导的激动剂的纤维化反应。新生儿 Timp3(-/-) 共培养物中发生了更强的反应，根据 Smad 信号传导和胶原蛋白表达的增加确定，这是由于 TNF 加工的增加和 TGF beta 1 提前蛋白水解成熟为其活性形式所致。使用遗传和药理学操作剖析了 TGF beta 1 和 TNF 之间的关系。 Timp3(-/-)/Tnf(-/-) 小鼠的 TGF β 1 水平低于 Timp3(-/-)，抗 TGF β 1 抗体 (1D11) 消除了异常的 TNF 反应，表明它们具有相互刺激作用，每次操作都消除了纤维化并改善了心脏功能。因此，TIMP3 是组织损伤反应中 TGF β 1 和 TNF 的常见先天调节因子。基质结合的 TIMP3 平衡抗炎和促炎过程，以实现建设性组织重塑。
The pleiotropic cytokines, transforming growth factor beta 1 (TGF beta 1), and tumor necrosis factor (TNF) play critical roles in tissue homeostasis in response to injury and are implicated in multiple human diseases and cancer. We reported that the loss of Timp3 (tissue inhibitor of metalloproteinase 3) leads to abnormal TNF signaling and cardiovascular function. Here we show that parallel deregulation of TGF beta 1 and TNF signaling in Timp3(-/-) mice amplifies their cross-talk at the onset of cardiac response to mechanical stress (pressure overload), resulting in fibrosis and early heart failure. Microarray analysis showed a distinct gene expression profile in Timp3(-/-) hearts, highlighting activation of TGF beta 1 signaling as a potential mechanism underlying fibrosis. Neonatal cardiomyocyte-cardiofibroblast co-cultures were established to measure fibrogenic response to agonists known to be induced following mechanical stress in vivo. A stronger response occurred in neonatal Timp3(-/-) cocultures, as determined by increased Smad signaling and collagen expression, due to increased TNF processing and precocious proteolytic maturation of TGF beta 1 to its active form. The relationship between TGF beta 1 and TNF was dissected using genetic and pharmacological manipulations. Timp3(-/-)/Tnf(-/-) mice had lower TGF beta 1 than Timp3(-/-), and anti-TGF beta 1 antibody (1D11) negated the abnormal TNF response, indicating their reciprocal stimulatory effects, with each manipulation abolishing fibrosis and improving heart function. Thus, TIMP3 is a common innate regulator of TGF beta 1 and TNF in tissue response to injury. The matrix-bound TIMP3 balances the anti-inflammatory and proinflammatory processes toward constructive tissue remodeling.