Distinct T cell/renal tubular epithelial cell interactions define differential chemokine production: Implications for tubulointerstitial injury in chronic glomerulonephritides
Distinct T cell/renal tubular epithelial cell interactions define differential chemokine production: Implications for tubulointerstitial injury in chronic glomerulonephritides
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DOI：
10.4049/jimmunol.164.6.3323
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发表时间：
2000-03-15
影响因子：
4.4
通讯作者：
Boumpas, DT
中科院分区：
文献类型：
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作者：
Kuroiwa, T;Schlimgen, R;Boumpas, DT
趋化因子可以促进间质纤维化，这反过来又是慢性肾小球肾炎（GN）中肾衰竭的强预测因子。包括肾小管上皮细胞（RTEC）的驻留肾细胞代表趋化因子表达的主要来源。因此，评估这些因素负责持续的趋化因子生产的RTEC在GN是至关重要的。间质性T细胞对这种表达的贡献，特别是它们与RTEC相互作用的精确成熟，知之甚少。活化T细胞/RTEC共培养诱导RTEC产生高水平的单核细胞趋化蛋白-1（MCP-1）、RANTES和IFN诱导蛋白-11。使用双室培养物和活化的T细胞质膜制备物，我们证明了细胞接触和可溶性因子都有助于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活化要求，因此，对于RANTES，细胞接触是必要的，但不是足够的。相比之下，无论是可溶性因子或细胞接触诱导MCP-1和IFN-诱导蛋白-10的生产，虽然这两种途径所需的最大响应。中和实验确定了促炎细胞因子如TNF-α、IL-1 β和IFN-γ以及膜分子如LFA-1、Cn 40配体和膜结合TNF-α在该过程中的关键作用。最后，T细胞/RTEC共培养上清液的趋化性生物测定表明MCP-1中和后单核细胞迁移减少80%，表明该趋化因子的主导作用。总之，浸润性T细胞激活肾小管细胞可以通过可溶性和细胞接触依赖性因子介导的差异化趋化因子产生来放大和维持局部炎症反应。认识到这种调节的多样性具有重要意义的选择潜在的治疗靶点在GN。
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 mature 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-ill 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-1 beta, and IFN-gamma as well as membrane molecules such as LFA-1, Cn40 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.