Wang Wansheng, Huang Xiao R, Li Allen G, Liu Fang, Li Jin-Hua, Truong Luan D, Wang Xiao J, Lan Hui Y
Department of Medicine, Baylor College of Medicine, One Baylor Plaza, Alkek N520, Houston, Texas 77030, USA.
J Am Soc Nephrol. 2005 May;16(5):1371-83. doi: 10.1681/ASN.2004121070. Epub 2005 Mar 23.
TGF-beta has been shown to play a critical role in anti-inflammation; however, the signaling mechanisms of TGF-beta in anti-inflammatory response remains largely unclear. This study reported that mice that overexpress latent TGF-beta1 on skin are protected against renal inflammation in a model of obstructive kidney disease and investigated the signaling mechanism of TGF-beta1 in inhibition of renal inflammation in vivo and in vitro. Seven days after urinary obstruction, wild-type mice developed severe renal inflammation, including massive T cell and macrophage infiltration and marked upregulation of IL-1beta, TNF-alpha, and intercellular adhesion molecule-1 (all P < 0.001). Surprising, renal inflammation was prevented in transgenic mice. This was associated with an increase in latent TGF-beta1 in circulation (a 10-fold increase) and renal tissues (a 2.5-fold increase). Further studies showed that inhibition of renal inflammation in TGF-beta1 transgenic mice was also associated with a marked upregulation of renal Smad7 and IkappaBalpha and a suppression of NF-kappaB activation in the diseased kidney (all P < 0.01). These in vivo findings suggested the importance of TGF-beta-NF-kappaB cross-talk signaling pathway in regulating renal inflammation. This was tested in vitro in a doxycycline-regulated Smad7-expressing renal tubular cell line. Overexpression of Smad7 was able to upregulate IkappaBalpha directly in a time- and dose-dependent manner, thereby inhibiting NF-kappaB activation and NF-kappaB-driven inflammatory response. In conclusion, latent TGF-beta may have protective roles in renal inflammation. Smad7-mediated inhibition of NF-kappaB activation via the induction of IkBalpha may be the central mechanism by which latent TGF-beta prevents renal inflammation.
转化生长因子-β（TGF-β）已被证明在抗炎中起关键作用；然而，TGF-β在抗炎反应中的信号传导机制仍不清楚。本研究报道，在皮肤上过表达潜伏性TGF-β1的小鼠在梗阻性肾病模型中可免受肾炎症影响，并研究了TGF-β1在体内和体外抑制肾炎症的信号传导机制。尿路梗阻7天后，野生型小鼠出现严重的肾炎症，包括大量T细胞和巨噬细胞浸润以及白细胞介素-1β、肿瘤坏死因子-α和细胞间黏附分子-1显著上调（均P<0.001）。令人惊讶的是，转基因小鼠的肾炎症得到了预防。这与循环中潜伏性TGF-β1增加（增加10倍）和肾组织中增加（增加2.5倍）有关。进一步研究表明，TGF-β1转基因小鼠肾炎症的抑制也与患病肾脏中肾Smad7和IκBα显著上调以及NF-κB激活受到抑制有关（均P<0.01）。这些体内研究结果表明TGF-β-NF-κB相互作用信号通路在调节肾炎症中的重要性。这在体外通过强力霉素调节表达Smad7的肾小管细胞系进行了验证。Smad7的过表达能够以时间和剂量依赖的方式直接上调IκBα，从而抑制NF-κB激活和NF-κB驱动的炎症反应。总之，潜伏性TGF-β可能在肾炎症中具有保护作用。Smad7通过诱导IκBα介导的对NF-κB激活的抑制可能是潜伏性TGF-β预防肾炎症的核心机制。
