IL-17 和 CD40 配体协同刺激糖尿病肾病的慢性化。
IL-17 and CD40 ligand synergistically stimulate the chronicity of diabetic nephropathy.
机构信息
Graduate Institute of Clinical Medical Science, College of Medicine, China Medical University, Taichung, Taiwan, China.
Department of Medicine, Division of Nephrology and Kidney Institute, China Medical University Hospital, Taichung, Taiwan, China.
出版信息
Nephrol Dial Transplant. 2018 Feb 1;33(2):248-256. doi: 10.1093/ndt/gfw397.
BACKGROUND
Early stages of diabetic nephropathy (DN) are characterized by an influx of inflammatory cells. Interactions between infiltrating T cells and podocytes may play an important role in the ongoing inflammatory response and remodelling. The aim of this study was to explore the role of IL-17 and CD40 ligand (CD40L) in DN.
METHODS
The study design involved a case series. Kidney biopsy samples of 69 patients with type 2 diabetes were assessed for the presence of CD4+ IL-17+ T cells. The number of CD4+ IL-17+ T cells were counted and correlated with clinical and laboratory findings. Additionally, advanced glycation end-products (AGEs) were added to cultured podocytes to imitate diabetic conditions and thus to elucidate the role of CD4+ IL-17+ T cells in renal sclerosis.
RESULTS
CD80 expression was detected in early phases of DN but was absent during diffused glomerurosclerosis in DN kidney specimens. In DN samples, CD40 expression was not only observed in most of the infiltrating cells, but also increased in podocytes and tubular epithelial cells. CD40L is locally expressed on infiltrating cells. CD4+ IL-17+ T cells were found in DN, and the number of CD4+ IL-17+ T cells was positively correlated with the deterioration in glomerular filtration rate (GFR). IL-17A was the key cytokine produced by CD4+ IL-17+ T cells. IL-17A levels were elevated in DN renal tissue and were correlated with declining GFR. IL-17 and CD40L synergistically enhanced IL-6, monocyte chemoattractant protein-1 (MCP-1), regulated on activation, normal T cell expressed and secreted (RANTES), transforming growth factor beta 1 (TGF-β1) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) production in vitro. AGEs induced podocyte activation with increasing expression of IL-17A, CD40 and TGF-β1 in vitro. Blockade with an anti-IL-17 monoclonal antibody reduced the expression of CD40 and TGF-β1, but increased the viability of cultured podocytes.
CONCLUSIONS
IL-17 and CD40L synergistically mediate the inflammatory response and remodelling associated with tissue injury and glomerular sclerosis in DN.
背景
糖尿病肾病（DN）的早期阶段以炎症细胞的涌入为特征。浸润 T 细胞与足细胞之间的相互作用可能在持续的炎症反应和重塑中发挥重要作用。本研究旨在探讨白细胞介素 17（IL-17）和 CD40 配体（CD40L）在 DN 中的作用。
方法
该研究设计为病例系列研究。评估 69 例 2 型糖尿病患者的肾活检样本中是否存在 CD4+IL-17+T 细胞。计数 CD4+IL-17+T 细胞的数量，并将其与临床和实验室发现相关联。此外，将晚期糖基化终产物（AGEs）添加到培养的足细胞中，以模拟糖尿病状态，从而阐明 CD4+IL-17+T 细胞在肾硬化中的作用。
结果
在 DN 的早期阶段检测到 CD80 表达，但在 DN 肾组织的弥漫性肾小球硬化中不存在。在 DN 样本中，CD40 表达不仅观察到在大多数浸润细胞中，而且在足细胞和肾小管上皮细胞中也增加。CD40L 局部表达于浸润细胞上。在 DN 中发现 CD4+IL-17+T 细胞，并且 CD4+IL-17+T 细胞的数量与肾小球滤过率（GFR）恶化呈正相关。IL-17A 是 CD4+IL-17+T 细胞产生的关键细胞因子。DN 肾组织中 IL-17A 水平升高，并与 GFR 下降相关。IL-17 和 CD40L 协同增强了体外 IL-6、单核细胞趋化蛋白-1（MCP-1）、调节激活正常 T 细胞表达和分泌因子（RANTES）、转化生长因子β1（TGF-β1）和核因子κB（NF-κB）的产生。AGEs 在体外诱导足细胞激活，增加 IL-17A、CD40 和 TGF-β1 的表达。用抗 IL-17 单克隆抗体阻断减少了 CD40 和 TGF-β1 的表达，但增加了培养的足细胞的活力。
结论
IL-17 和 CD40L 协同介导与组织损伤和肾小球硬化相关的炎症反应和重塑，在 DN 中起作用。
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