IL-18 mediates proapoptotic signaling in renal tubular cells through a Fas ligand-dependent mechanism
| Autor: | Ethan I. Franke, Matthew T. Campbell, Hiroshi Asanuma, Kirstan K. Meldrum, Karen L. Hile, Brian A. VanderBrink, Hongji Zhang |
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| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Male
Fas Ligand Protein Physiology medicine.medical_treatment Blotting Western Apoptosis Enzyme-Linked Immunosorbent Assay Mice Transgenic urologic and male genital diseases Transfection Fas ligand Kidney Tubules Proximal Mice medicine Renal fibrosis In Situ Nick-End Labeling Animals Humans RNA Small Interfering Caspase Cells Cultured Kidney biology Reverse Transcriptase Polymerase Chain Reaction Interleukin-18 Articles Flow Cytometry Cell biology Mice Inbred C57BL Cytokine medicine.anatomical_structure Caspases biology.protein Intercellular Signaling Peptides and Proteins Signal transduction Signal Transduction Ureteral Obstruction |
| Popis: | Renal tubular cell apoptosis is a significant component of obstruction-induced renal injury, and it results in a progressive loss in renal parenchymal mass during renal obstruction. Although IL-18 is an important mediator of inflammatory renal disease and renal fibrosis, its role in obstruction-induced renal tubular cell apoptosis remains unclear. To study this, male C57BL6 wild-type mice and C57BL6 mice transgenic for human IL-18-binding protein (IL-18BP Tg) were subjected to renal obstruction vs. sham operation. The kidneys were harvested after 1 or 2 wk and analyzed for IL-18 production, apoptosis, caspase activity, and Fas/Fas Ligand (FasL) expression. HK-2 cells were similarly analyzed for apoptosis and proapoptotic signaling following 3 days of direct exposure to IL-18 vs. control media. Renal obstruction induced a significant increase in IL-18 production, renal tubular cell apoptosis, caspase activation, and FasL expression. IL-18 neutralization, on the other hand, significantly reduced obstruction-induced apoptosis, caspase-8 and caspase-3 activity, and FasL expression. In vitro experiments similarly demonstrate that IL-18 stimulation induces apoptosis, FasL expression, and increases active caspase-8 and caspase-3 expression in a dose-dependent fashion. siRNA knockdown of FasL gene expression, however, significantly reduced IL-18-induced apoptosis. This study reveals that IL-18 is a significant mediator of obstruction-induced tubular cell apoptosis, and it demonstrates that IL-18 stimulates proapoptotic signaling through a FasL-dependent mechanism. |
| Databáze: | OpenAIRE |
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