title: MCP-1 induces inflammatory activation of human tubular epithelial cells: involvement of the transcription factors, nuclear factor-kappaB and activating protein-1.
abstract: 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.
authors.affiliation: Department of Internal Medicine, Division of Cardiology, Ruperto Carola University, Heidelberg, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Viedt
authors.forename: Ralph
authors.initials: R
authors.lastname: Dechend
authors.forename: Jianwei
authors.initials: J
authors.lastname: Fei
authors.forename: Gertrud M
authors.initials: GM
authors.lastname: Hänsch
authors.forename: Jörg
authors.initials: J
authors.lastname: Kreuzer
authors.forename: Stephan R
authors.initials: SR
authors.lastname: Orth
mesh_terms: D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism / Q000494:pharmacology*; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D007684:Kidney Tubules / Q000187:drug effects* / Q000276:immunology; D016328:NF-kappa B / Q000502:physiology*; D009393:Nephritis / Q000209:etiology*; D012333:RNA, Messenger / Q000032:analysis; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000502:physiology*
chemical_list: C515334:CCR2 protein, human; D018932:Chemokine CCL2; D015850:Interleukin-6; D016328:NF-kappa B; D012333:RNA, Messenger; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D018808:Transcription Factor AP-1; D018799:Intercellular Adhesion Molecule-1