Luo Dong Dong, Fielding Ceri, Phillips Aled, Fraser Donald
Institute of Nephrology, Cardiff University, UK.
Nephrol Dial Transplant. 2009 Sep;24(9):2655-65. doi: 10.1093/ndt/gfp208. Epub 2009 May 6.
Increased transforming growth factor beta-1 (TGF beta) expression in the kidney is central not only to the pathogenesis of tubulointerstitial fibrosis but also in repair following acute injury. Recent work suggests that pro-inflammatory cytokines may determine epithelial cell responses to TGF beta in the contexts of acute injury and chronic wounding.
In this study, we examined the effects of interleukin-1 beta (IL-1) on proximal tubular cell (PTC) response to TGF beta.
IL-1 induced the rapid activation of NF-kappaB in PTC. This was associated with inhibition of Smad2 and Smad3 signalling. NF-kappaB activation by IL-1 was transient, with a change from p65/p50 heterodimer to p50/p50 homodimer formation by 24 h and a switch to enhanced Smad signalling response to TGF beta. This was associated with IL-6 generation and prevented by IL-6 receptor blockade.
In summary, IL-1 has a biphasic effect on PTC TGF beta signalling, with early NF-kappaB-mediated inhibition and delayed sensitization via an autocrine IL-6 loop. These results provide mechanistic insight into how acute and chronic inflammation help define epithelial cell response to TGF beta, and hence how TGF beta can have apparently contradictory roles, being involved in controlled healing following acute injury on one hand, yet the principal promoter of scarring in chronic disease on the other.
肾脏中转化生长因子β-1（TGFβ）表达增加不仅是肾小管间质纤维化发病机制的核心，也是急性损伤后修复过程的关键。近期研究表明，促炎细胞因子可能在急性损伤和慢性创伤情况下决定上皮细胞对TGFβ的反应。
在本研究中，我们检测了白细胞介素-1β（IL-1）对近端肾小管细胞（PTC）对TGFβ反应的影响。
IL-1诱导PTC中NF-κB的快速激活。这与Smad2和Smad3信号传导的抑制相关。IL-1介导的NF-κB激活是短暂的，24小时时从p65/p50异二聚体转变为p50/p50同二聚体形成，并转变为对TGFβ增强的Smad信号反应。这与IL-6的产生相关，并可通过IL-6受体阻断来预防。
总之，IL-1对PTC的TGFβ信号传导具有双相作用，早期通过NF-κB介导抑制，后期通过自分泌IL-6环实现致敏。这些结果为急性和慢性炎症如何帮助定义上皮细胞对TGFβ的反应提供了机制性见解，从而解释了TGFβ如何具有明显矛盾的作用，一方面参与急性损伤后的可控愈合，另一方面却是慢性疾病中瘢痕形成的主要促进因素。
