Profibrotic effect of interleukin-18 in HK-2 cells is dependent on stimulation of the toll-like receptor 4 (TLR4) promoter and increased TLR4 expression

Kirstan K. Meldrum, Hongji Zhang, Karen L. Hile, Lyle L. Moldower, Zizheng Dong, Daniel R. Meldrum

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

IL-18 is an important mediator of obstruction-induced renal fibrosis and tubular epithelial cell injury independent of TGF-β1 activity. We sought to determine whether the profibrotic effect of IL-18 is mediated through Toll-like receptor 4 (TLR4). Male C57BL6 wild type and mice transgenic for human IL-18-binding protein were subjected to left unilateral ureteral obstruction versus sham operation. The kidneys were harvested 1 week postoperatively and analyzed for IL-18 production and TLR4 expression. In a separate arm, renal tubular epithelial cells (HK-2) were directly stimulated with IL-18 in the presence or absence of a TLR4 agonist, TLR4 antagonist, or TLR4 siRNA knockdown. Cell lysates were analyzed for TLR4, α-smooth muscle actin, and E-cadherin expression. TLR4 promotor activity, as well as AP-1 activation and the effect of AP-1 knockdown on TLR4 expression, was evaluated in HK-2 cells in response to IL-18 stimulation. The results demonstrate that IL-18 induces TLR4 expression during unilateral ureteral obstruction and induces TLR4 expression in HK-2 cells via AP-1 activation. Inhibition of TLR4 or knockdown of TLR4 gene expression in turn prevents IL-18-inducedprofibroticchangesinHK-2cells. Theseresultssuggest that IL-18 induces profibrotic changes in tubular epithelial cells via increased TLR4 expression/signaling.

Original languageEnglish
Pages (from-to)40391-40399
Number of pages9
JournalJournal of Biological Chemistry
Volume287
Issue number48
DOIs
StatePublished - Nov 23 2012

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Toll-Like Receptor 4
Interleukin-18
Transcription Factor AP-1
Ureteral Obstruction
Epithelial Cells
Kidney
Chemical activation
Cadherins
Gene expression
Small Interfering RNA
Transgenic Mice
Smooth Muscle
Muscle
Actins
Fibrosis

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Profibrotic effect of interleukin-18 in HK-2 cells is dependent on stimulation of the toll-like receptor 4 (TLR4) promoter and increased TLR4 expression. / Meldrum, Kirstan K.; Zhang, Hongji; Hile, Karen L.; Moldower, Lyle L.; Dong, Zizheng; Meldrum, Daniel R.

In: Journal of Biological Chemistry, Vol. 287, No. 48, 23.11.2012, p. 40391-40399.

Research output: Contribution to journalArticle

Meldrum, Kirstan K. ; Zhang, Hongji ; Hile, Karen L. ; Moldower, Lyle L. ; Dong, Zizheng ; Meldrum, Daniel R. / Profibrotic effect of interleukin-18 in HK-2 cells is dependent on stimulation of the toll-like receptor 4 (TLR4) promoter and increased TLR4 expression. In: Journal of Biological Chemistry. 2012 ; Vol. 287, No. 48. pp. 40391-40399.
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