Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus MC-University Medical Center Rotterdam, Rotterdam, the Netherlands.
PLoS One. 2013 May 22;8(5):e64916. doi: 10.1371/journal.pone.0064916. Print 2013.
Renal tubular epithelial cells (TECs) are one of the main targets of inflammatory insults during interstitial nephritis and kidney transplant rejection. While Th1 cells are know to be essential in the pathogenesis of rejection, the role of Th17 is still under debate. We hypothesize that TECs modulate the outcome of rejection process by production of distinct chemokines and cytokines that determine the attraction of different T-cell subsets. Therefore, we studied differential effects of activated human renal epithelial cells on T-cell migration.
Human primary TECs were stimulated by IFN-γ and TNF-α in vitro. Chemokines and cytokines produced by activated TECs were measured using Luminex or ELISA. Chemotaxis assay was performed using activated peripheral blood mononuclear cells composed of CD4+CXCR3+ and CD4+CCR6+ T cells migrating towards stimulated and unstimulated TECs.
While activated TECs secreted abundant amounts of the pro-inflammatory cytokines IL-6 and IL-8, the T helper cell differentiation cytokines IL-1β, IL-12p70, IL-23 or TGF-β1 were not produced. The production of Th1 chemokines CXCL9, CXCL10 and CCL5 were significantly upregulated after TEC stimulation. In contrast, Th17 chemokine CCL20 could not be detected. Finally, activated TECs attracted significantly higher numbers of CD4+CXCR3+ T cells as compared to unstimulated TECs. No migration of CD4+CCR6+ T cells could be observed.
Activated primary renal tubular epithelial cells do not attract Th17 cells nor produce cytokines promoting Th17 cell differentiation in our experimental system mimicking the proinflammatory microenvironment of rejection.
肾小管上皮细胞 (TEC) 是间质性肾炎和肾移植排斥反应过程中炎症损伤的主要靶细胞之一。虽然 Th1 细胞在排斥反应的发病机制中被认为是必不可少的，但 Th17 的作用仍存在争议。我们假设 TEC 通过产生不同的趋化因子和细胞因子来调节排斥过程的结果，这些趋化因子和细胞因子决定了不同 T 细胞亚群的吸引力。因此，我们研究了活化的人肾小管上皮细胞对 T 细胞迁移的不同影响。
体外用人 IFN-γ 和 TNF-α 刺激人原代 TEC。使用 Luminex 或 ELISA 测量活化的 TEC 产生的趋化因子和细胞因子。使用由 CD4+CXCR3+和 CD4+CCR6+ T 细胞组成的活化外周血单个核细胞进行趋化性测定，这些细胞向受刺激和未受刺激的 TEC 迁移。
虽然活化的 TEC 分泌大量促炎细胞因子 IL-6 和 IL-8，但不产生 Th1 细胞分化细胞因子 IL-1β、IL-12p70、IL-23 或 TGF-β1。TEC 刺激后，Th1 趋化因子 CXCL9、CXCL10 和 CCL5 的产生显著上调。相比之下，未检测到 Th17 趋化因子 CCL20。最后，与未刺激的 TEC 相比，活化的 TEC 吸引了明显更多数量的 CD4+CXCR3+ T 细胞。未观察到 CD4+CCR6+ T 细胞的迁移。
在我们模拟排斥反应前炎性微环境的实验系统中，活化的原代肾小管上皮细胞不会吸引 Th17 细胞，也不会产生促进 Th17 细胞分化的细胞因子。
