Viedt Christiane, Dechend Ralph, Fei Jianwei, Hänsch Gertrud M, Kreuzer Jörg, Orth Stephan R
Department of Internal Medicine, Division of Cardiology, Ruperto Carola University, Heidelberg, Germany.
J Am Soc Nephrol. 2002 Jun;13(6):1534-47. doi: 10.1097/01.asn.0000015609.31253.7f.
Monocyte chemoattractant protein-1 (MCP-1) is a potent chemokine synthesized by several cell types, e.g., inflammatory cells, such as monocytes, and resident renal cells, such as human tubular epithelial cells (TECs). Besides induction of monocyte recruitment, MCP-1 has been suggested to induce non-leukocytes to produce cytokines and adhesion molecules. Inflammation of the tubulointerstitium is a hallmark of many renal diseases and contributes to progression of renal failure; the purpose therefore of this study was to investigate the influence of MCP-1 on markers of inflammatory activation in human TECs. MCP-1 stimulated interleukin-6 (IL-6) secretion and intercellular adhesion molecule-1 (ICAM-1) synthesis in a time- and dose-dependent manner. In parallel, MCP-1 increased IL-6 and ICAM-1 mRNA expression in human TECs. Pretreatment with pertussis toxin, GF109203X, BAPTA-AM, and pyrrolidine dithiocarbamate inhibited MCP-1-dependent IL-6 and ICAM-1 synthesis, suggesting the involvement of Gi-proteins, protein kinase C, intracellular Ca(2+), and nuclear factor-kappaB (NF-kappaB) in MCP-1 signaling. Using electrophoretic gel mobility shift assay, we observed that MCP-1 stimulated binding activity of NF-kappaB. Binding activity of the activator protein-1 (AP-1), which has been implicated to regulate induction of the IL-6 gene together with NF-kappaB, was also stimulated by MCP-1. In the present experiments, NF-kappaB and AP-1 were involved in the MCP-1-mediated induction of IL-6, as demonstrated by cis element double-stranded (decoy) oligonucleotides (ODN). In contrast to IL-6 release, MCP-1-induced ICAM-1 expression was predominantly dependent on NF-kappaB activation. These results document for the first time that MCP-1 induces an inflammatory response in human TECs. This may be an important new mechanism in the pathogenesis of tubulointerstitial inflammation.
单核细胞趋化蛋白-1（MCP-1）是一种由多种细胞类型合成的强效趋化因子，例如炎症细胞，如单核细胞，以及肾脏驻留细胞，如人肾小管上皮细胞（TECs）。除了诱导单核细胞募集外，MCP-1还被认为可诱导非白细胞产生细胞因子和黏附分子。肾小管间质炎症是许多肾脏疾病的标志，并促进肾衰竭的进展；因此，本研究的目的是探讨MCP-1对人TECs中炎症激活标志物的影响。MCP-1以时间和剂量依赖性方式刺激白细胞介素-6（IL-6）分泌和细胞间黏附分子-1（ICAM-1）合成。同时，MCP-1增加了人TECs中IL-6和ICAM-1 mRNA的表达。用百日咳毒素、GF109203X、BAPTA-AM和吡咯烷二硫代氨基甲酸盐预处理可抑制MCP-1依赖性IL-6和ICAM-1的合成，提示Gi蛋白、蛋白激酶C、细胞内Ca(2+)和核因子-κB（NF-κB）参与了MCP-1信号传导。使用电泳凝胶迁移率变动分析，我们观察到MCP-1刺激了NF-κB的结合活性。与NF-κB一起参与调节IL-6基因诱导的激活蛋白-1（AP-1）的结合活性也受到MCP-1的刺激。在本实验中，如顺式元件双链（诱饵）寡核苷酸（ODN）所示，NF-κB和AP-1参与了MCP-1介导的IL-6诱导。与IL-6释放相反，MCP-1诱导的ICAM-1表达主要依赖于NF-κB激活。这些结果首次证明MCP-1在人TECs中诱导炎症反应。这可能是肾小管间质炎症发病机制中的一个重要新机制。
