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

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14 Scopus citations


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


ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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