Document Detail


Proinflammatory/Profibrotic Effects of Interleukin-17A on Human Proximal Tubule Epithelium.
MedLine Citation:
PMID:  20924205     Owner:  NLM     Status:  In-Data-Review    
Abstract/OtherAbstract:
Background/Aims: Interleukin-17A (IL-17A) is a T cell-derived inflammatory cytokine that is upregulated during renal allograft rejection. The present study sought to further describe the IL-17A-mediated proinflammatory/profibrotic activity of proximal tubule epithelium that may contribute to allograft rejection. Methods: Immortalized (HK-2) and primary (HRPTEpiC) human proximal tubule epithelial cells were utilized for this study. Profibrotic gene alterations were examined by real-time quantitative PCR. Inflammatory mediator secretion was examined by multiplex bead-based detection of secreted proteins. Immunofluorescence microscopy and immunoblotting were utilized to examine alterations in junctional protein expression and cell morphology. Results: In HK-2 cells IL-17A significantly downregulated the expression of the proepithelial gene CDH1 (E-cadherin) while the proinflammatory/profibrotic genes CTGF, CD44 and TGFBR1 were significantly increased. IL-17A also increased the secretion of fractalkine, G-CSF, GM-CSF, VEGF, IL-6 and IL-8. In HRPTEpiC 100 ng/ml IL-17A upregulated the proinflammatory/profibrotic genes ACTA2, CCL2, CHMP1A, CTGF, FN1, IL6, FSP1, SMAD1, SMAD5, TGFB1 and TGFBR2 while treatment with a reduced concentration of IL-17A (0.1 ng/ml) decreased SMAD5, TGFB1 and PDGFRB expression. Changes in ZO-1 and E-cadherin protein expression and cell morphology were examined following IL-17A treatment as indicators of epithelial-to-mesenchymal transition. IL-17A decreased ZO-1 expression in HK-2 and HRPTEpiC; however, E-cadherin was only reduced in HK-2 cells. Neither HK-2 nor HRPTEpiC assumed an elongated, fibroblast-like morphology following IL-17A treatment. Conclusions: IL-17A directly mediates proximal tubule epithelial cell proinflammatory/profibrotic activity as demonstrated by the alteration in genes associated with extracellular matrix remodeling and cell-cell interaction, and stimulation of inflammatory mediator and immune cell chemoattractant secretion. Additionally, IL-17A may have a negative impact on barrier integrity as indicated by ZO-1 downregulation.
Authors:
Paul L Dudas; Sarah L Sague; M Merle Elloso; Francis X Farrell
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Publication Detail:
Type:  Journal Article     Date:  2010-10-02
Journal Detail:
Title:  Nephron. Experimental nephrology     Volume:  117     ISSN:  1660-2129     ISO Abbreviation:  Nephron Exp. Nephrol.     Publication Date:  2011  
Date Detail:
Created Date:  2011-04-05     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101159770     Medline TA:  Nephron Exp Nephrol     Country:  Switzerland    
Other Details:
Languages:  eng     Pagination:  e114-23     Citation Subset:  IM    
Copyright Information:
Copyright © 2010 S. Karger AG, Basel.
Affiliation:
Department of Immunology Research, Centocor Research and Development, Inc., Radnor, Pa., USA.
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