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首页> 外文期刊>The Journal of Immunology: Official Journal of the American Association of Immunologists >Distinct T cell/renal tubular epithelial cell interactions define differential chemokine production: implications for tubulointerstitial injury in chronic glomerulonephritides.
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Distinct T cell/renal tubular epithelial cell interactions define differential chemokine production: implications for tubulointerstitial injury in chronic glomerulonephritides.

机译：不同的T细胞/肾小管上皮细胞相互作用定义了不同的趋化因子产生：对慢性肾小球素肾小管间质损伤的影响。

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摘要

Chemokines can promote interstitial fibrosis that is, in turn, a strong predictor of renal failure in chronic glomerulonephritides (GN). Resident renal cells, including renal tubular epithelial cells (RTEC), represent a prominent source of chemokine expression. Evaluating those factors responsible for sustained chemokine production by RTEC during GN is therefore crucial. The contribution of interstitial T cells to such expression, and in particular the precise nature of their interactions with RTEC, are poorly understood. Activated T cell/RTEC coculture induced production of high levels of monocyte chemoattractant protein-1 (MCP-1), RANTES, and IFN-inducible protein-10 from RTEC. Using double-chamber cultures and activated T cell plasma membrane preparations we demonstrated that both cell contact and soluble factors contributed to RTEC chemokine production. Importantly, different chemokines exhibited distinct activation requirements. Thus, for RANTES cell contact was essential, but not sufficient. In contrast, either soluble factors or cell contact induced MCP-1 and IFN-inducible protein-10 production, although both pathways were required for a maximal response. Neutralization experiments identified critical roles in this process for proinflammatory cytokines such as TNF-alpha, IL-1beta, and IFN-gamma as well as membrane molecules such as LFA-1, CD40 ligand, and membrane bound TNF-alpha. Finally, chemotactic bioassays of T cell/RTEC coculture supernatants demonstrated 80% reduction of monocyte migration following MCP-1 neutralization, indicating a dominant role for this chemokine. In summary, activation of renal tubular cells by infiltrating T cells can amplify and perpetuate local inflammatory responses through chemokine production differentially mediated by soluble and cell contact-dependent factors. Recognition of this regulatory diversity has important implications in the choice of potential therapeutic targets in GN.
机译：趋化因子可促进间质纤维化，进而是慢性肾小球性肾炎（GN）肾衰竭的有力预测指标。包括肾小管上皮细胞（RTEC）在内的常驻肾细胞代表趋化因子表达的重要来源。因此，评估导致GN期间RTEC持续产生趋化因子的因素至关重要。间质T细胞对这种表达的贡献，特别是它们与RTEC相互作用的确切性质，了解得很少。活化的T细胞/ RTEC共培养可诱导RTEC生产高水平的单核细胞趋化蛋白1（MCP-1），RANTES和IFN诱导型蛋白10。使用双室培养和活化的T细胞质膜制备，我们证明细胞接触和可溶性因子均有助于RTEC趋化因子的产生。重要的是，不同的趋化因子表现出不同的激活要求。因此，对于RANTES，细胞接触是必不可少的，但还不够。相反，可溶性因子或细胞接触诱导了MCP-1和IFN诱导的蛋白10的产生，尽管两种途径都需要最大的响应。中和实验确定了该过程中促炎细胞因子（例如TNF-α，IL-1beta和IFN-γ）以及膜分子（例如LFA-1，CD40配体和膜结合的TNF-α）的关键作用。最终，T细胞/ RTEC共培养上清液的趋化生物测定表明，MCP-1中和后单核细胞迁移减少了80％，这表明该趋化因子起主要作用。总之，通过渗透性T细胞激活肾小管细胞可以通过由可溶性和细胞接触依赖性因子差异介导的趋化因子产生来放大和延续局部炎症反应。认识到这种调节多样性对GN中潜在治疗靶标的选择具有重要意义。

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