title: IL-8 amplifies CD40/CD154-mediated ICAM-1 production via the CXCR-1 receptor and p38-MAPK pathway in human renal proximal tubule cells.
abstract: Activation of the CD40 receptor by its cognate ligand, CD154, results in interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) production and increased intercellular adhesion molecule-1 (ICAM-1) expression in proximal tubule cells (PTCs). The independent role of these two proinflammatory chemokines, IL-8 and MCP-1, in inciting an inflammatory response in PTCs was explored. Exposure of primary cultures of human renal PTCs to recombinant IL-8 and MCP-1 resulted in increased ICAM-1 expression measured by quantitative real-time PCR, but confirmed only for IL-8 by immunoblot. The mechanism of action of IL-8 was explored in further detail. Immunohistochemistry identified both the CXCR-1 and CXCR-2 receptors, confirmed by RT-PCR, immunoprecipitation, immunoblot, and FACS analysis. IL-8 increased ICAM-1 expression only via the CXCR-1 receptor, which in turn resulted in activation of the p38 mitogen-activated protein kinase (MAPK) pathway; neither the extracellular signal-related kinase (ERK) 1/2 MAPK pathway nor the stress-activated protein kinase (SAPK)/c-Jun NH(2) terminal kinase (JNK) pathway was involved. CD154/CD40-mediated ICAM-1 upregulation was not affected by preincubation of monolayers with the CXCR-1 blocking antibody, indicating that ICAM-1 expression occurs independent of CD154-mediated IL-8 production. Coincubation of monolayers with both CD154 and IL-8 resulted in a greater ICAM-1 response than either compound alone. We conclude that in human renal PTCs, IL-8 upregulates ICAM-1 production by engaging the CXCR-1 receptor and p38 MAPK signaling pathway. This cascade of events is independent of CD40/CD154-mediated IL-8 stimulation and ICAM-1 production and serves to amplify the inflammatory response.
authors.affiliation: Department of Medicine, Div. of Nephrology, School of Medicine, HSC T-16 Rm-080, State Univ. of NY at Stony Brook, Stony Brook, NY 11794, USA.
authors.forename: Hongye
authors.initials: H
authors.lastname: Li
authors.forename: Edward P
authors.initials: EP
authors.lastname: Nord
mesh_terms: D019013:CD40 Antigens / Q000378:metabolism; D023201:CD40 Ligand / Q000378:metabolism; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D016209:Interleukin-8 / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D023062:Receptors, Interleukin-8A / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: C111835:CCL2 protein, human; D019013:CD40 Antigens; C508606:CXCL8 protein, human; D018932:Chemokine CCL2; D016209:Interleukin-8; D023062:Receptors, Interleukin-8A; D018799:Intercellular Adhesion Molecule-1; D023201:CD40 Ligand; D048051:p38 Mitogen-Activated Protein Kinases