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This Article Full Text Full Text (PDF) All Versions of this Article: 296/2/F438    most recent 90214.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Li, H. Articles by Nord, E. P. Search for Related Content PubMed PubMed Citation Articles by Li, H. Articles by Nord, E. P.

IL-8 amplifies CD40/CD154-mediated ICAM-1 production via the CXCR-1 receptor and p38-MAPK pathway in human renal proximal tubule cells

Department of Medicine, Division of Nephrology, School of Medicine, State University of New York at Stony Brook, Stony Brook, New York

Submitted 26 March 2008 ; accepted in final form 24 July 2008

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 NH₂ 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.

chemokines; IL-8 receptor; mitogen-activated protein kinases; interstitial inflammation; kidney cells