TNF-α and IL-1β-mediated regulation of MMP-9 and TIMP-1 in renal proximal tubular cells

Larine E. Nee, Tara McMorrow, Eric Campbell, Craig Slattery, Michael P. Ryan*

*Corresponding author for this work

Research output: Contribution to journalArticle

69 Citations (Scopus)

Abstract

Background. Tubulointerstitial fibrosis is a morphologic hallmark of chronic kidney disease and is a key factor in the prediction of progression to end-stage renal failure. Disruption of tubular basement membrane and interstitial extracellular matrix (ECM) via cytokine-induced alterations in matrix metalloproteinases (MMPs), and tissue inhibitors of metalloproteinases (TIMPs) may be an important mechanism in this process. The presence of the proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) and their effects on proximal tubular cells may be critical in this process. Methods. Human proximal tubular cells were cultured in hormonally defined medium. Cells at 80% confluency were exposed to TNF-α (0.1 to 100 ng/mL) or IL-1β (0.1 to 100 ng/mL) or a combination of both for 48 hours. Activity and expression of MMP-9 was examined by gelatin zymography and Western blot analysis. TIMP-1 expression was analyzed by Western blotting. Signaling through cytokine receptors, protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) pathways was investigated. Results. TNF-α but not IL-1β resulted in a dose-dependent increase in the latent form of MMP-9. TIMP-1 was decreased by treatment with either TNF-α or IL-1β. Cotreatment with IL-1β abolished the induction of MMP-9 but augmented the inhibition of TIMP-1 in the presence of TNF-α. Inhibition of PKC provided evidence of the importance of this pathway in mediating the cytokine-induced suppression of TIMP-1 in human kidney (HK-2) cells. Activation of the extracellular signal-regulated protein kinase (ERK1/2) MAPK mediated the up-regulation of MMP-9 by TNF-α whereas p38 was found to be involved in the IL-1β-mediated inhibition of TNF-α-stimulated MMP-9. Conclusion. The differential effects of TNF-α and IL-1β on proximal tubular MMP-9 and TIMP-1 expression are mediated through the TNF-RI, the IL-1-RI and the different signaling pathways of PKC, ERK1/2, and p38 MAPK. These findings may provide new insights into the role of proinflammatory cytokines TNF-α and IL-1β in the development and possible therapeutic intervention in tubulointerstitial fibrosis.

Original languageEnglish
Pages (from-to)1376-1386
Number of pages11
JournalKidney International
Volume66
Issue number4
DOIs
Publication statusPublished - Oct 2004
Externally publishedYes

Keywords

  • ERK1/2
  • Extracellular matrix
  • Fibrosis
  • IL-1-RI
  • IL-1β
  • MMP-9
  • p38 MAPK
  • PKC
  • TIMP-1
  • TNF-RI
  • TNF-α

ASJC Scopus subject areas

  • Nephrology

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