title: Interaction between proximal tubular epithelial cells and infiltrating monocytes/T cells in the proteinuric state.
abstract: We hypothesize an interaction between T cells/monocytes and the tubules in the development of tubulointerstitial injury in chronic proteinuric nephropathy. We established in vitro co-culture systems of proximal tubular epithelial cells (PTEC) and T cells/monocytes to study the contribution of soluble factors and cell-to-cell contact in the development of tubulointerstitial injury. The release of monocyte chemoattractant protein-1 (MCP1 or CCL2), Regulated upon Activation, normal T cell Expressed and Secreted (RANTES or CCL5), soluble intracellular adhesion molecules-1 (sICAM-1), or interleukin-6 (IL-6) was increased in PTEC following apical exposure to human serum albumin (HSA). The release of CCL2, CCL5, or sICAM-1 from PTEC was enhanced by contact of monocytes/T cells on the basolateral surface. Tumor necrosis factor-alpha (TNF-alpha) and IL-1beta are important soluble factors as suggested by the blocking effect of antibodies (Abs) against TNF-alpha or IL-1beta but not against other cytokines. The percentage of CD4+ T cells expressing both chemokine receptors, CCR2 and CCR5, was increased after culturing with supernatant from the apical or basolateral surface of PTEC following apical exposure to HSA. However, only CCR2 was upregulated in CD8+ T cells, whereas CCR5 expression was increased in monocytes. The chemotaxis of CD4+ or CD8+ T cells to supernatant from PTEC upon apical exposure to HSA was reduced with neutralizing Abs against CCL5 and/or CCL2, whereas the chemotaxis of monocytes was only reduced by anti-CCL5 but not by anti-CCL2. In summary, chemokines released by HSA-activated PTEC are amplified by monocytes/T cells. Mediators released by HSA-activated PTEC can differentially modulate the expression of chemokine receptors in monocytes/T cells and hence, alter their chemotaxis towards activated PTEC. These interactions are pivotal in the development of tubulointerstitial injury.
authors.affiliation: Division of Nephrology, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China. knlai@hku.hk
authors.forename: K N
authors.initials: KN
authors.lastname: Lai
authors.forename: J C K
authors.initials: JC
authors.lastname: Leung
authors.forename: L Y Y
authors.initials: LY
authors.lastname: Chan
authors.forename: H
authors.initials: H
authors.lastname: Guo
authors.forename: S C W
authors.initials: SC
authors.lastname: Tang
mesh_terms: D002450:Cell Communication / Q000502:physiology*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D018946:Chemokine CCL5; D019742:Chemokines, CC / Q000235:genetics / Q000378:metabolism; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology; D018920:Coculture Techniques; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009000:Monocytes / Q000473:pathology* / Q000502:physiology; D011507:Proteinuria / Q000473:pathology* / Q000503:physiopathology; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism; D012709:Serum Albumin / Q000494:pharmacology; D013601:T-Lymphocytes / Q000473:pathology* / Q000502:physiology
chemical_list: C111835:CCL2 protein, human; C483024:CCL5 protein, human; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D019742:Chemokines, CC; D053645:Interleukin-2 Receptor alpha Subunit; D015850:Interleukin-6; D019707:Receptors, Chemokine; D012709:Serum Albumin; D018799:Intercellular Adhesion Molecule-1