title: IL-18 induces profibrotic renal tubular cell injury via STAT3 activation.
abstract: IL-18 is an important mediator of obstruction-induced renal fibrosis and renal tubular epithelial cell (TEC) injury. IL-18's proinflammatory properties have been attributed, in part, to NF-κB activation and the stimulation of cytokine gene expression; however, STAT3 has increasingly been shown to mediate renal fibrotic injury. We therefore hypothesized that IL-18 mediates profibrotic TEC injury via STAT3 activation. Male C57BL6 wild-type mice and transgenic mice for human IL-18-binding protein were subjected to unilateral ureteral obstruction or sham operation. The kidneys were harvested 1 or 2 wk afterward and analyzed for active STAT3 (p-STAT3) expression (Western blotting, immunohistochemistry) and suppressor of cytokine signaling 3 (SOCS3) expression. In a separate arm, renal tubular cells (HK-2) were directly stimulated with IL-18 for 2 days with or without the STAT3 inhibitor S3I-201 (50 μM). Cell lysates were then analyzed for p-STAT3 and SOCS3 expression, profibrotic cellular changes (collagen and α-SMA expression), and tubular cell apoptosis. p-STAT3 and SOCS3 expression increased significantly in response to obstruction; however, a significant reduction in p-STAT3 and SOCS3 expression occurred following 1 wk, but not 2 wk, of obstruction in the presence of IL-18 neutralization. In vitro results similarly demonstrate increased p-STAT3, SOCS3, α-SMA, and collagen III expression, and increased collagen production and TEC apoptosis in response to IL-18 stimulation, but the response was significantly diminished in the presence of STAT3 inhibition. These results demonstrate that IL-18-induces profibrotic cellular changes and collagen production in TECs via STAT3 activation.
authors.affiliation: Pediatric Urology, Univ. of Florida, Gainesville, FL 32610.
authors.forename: Futoshi
authors.initials: F
authors.lastname: Matsui
authors.forename: Audrey
authors.initials: A
authors.lastname: Rhee
authors.forename: Karen L
authors.initials: KL
authors.lastname: Hile
authors.forename: Hongji
authors.initials: H
authors.lastname: Zhang
authors.forename: Kirstan K
authors.initials: KK
authors.lastname: Meldrum
mesh_terms: D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D003094:Collagen / Q000378:metabolism; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000378:metabolism; D005355:Fibrosis; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D020382:Interleukin-18 / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009400:Nephrosclerosis / Q000378:metabolism* / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism* / Q000502:physiology; D014517:Ureteral Obstruction / Q000378:metabolism / Q000473:pathology
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18; C106644:SOCS3 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C491411:Socs3 protein, mouse; C494087:Stat3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C118370:interleukin-18 binding protein; D003094:Collagen
keywords: STAT; fibrosis; fibrosis, ureteral obstruction; interleukin-18; kidney
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