Effect of proinflammatory cytokines, tumor necrosis factor-α and interferon-γ on epithelial barrier function and matrix metalloproteinase-9 in madin darby canine kidney cells

Amanda K. Leone, Jennifer A. Chun, Christopher L. Koehler, Jonathan Caranto, Jonathan M. King

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Background: Elevated matrix metalloproteinase-9 production during inflammation may be deleterious to epithelial barrier function. Therefore we examined the effect of proinflammatory cytokines on the expression and regulation of matrix metalloproteinase-9 in a model renal epithelial cell system. Tight junctions limit diffusion between compartments and permit directional transport of solutes. Impairment of these junctional complexes by proteolysis may contribute to renal failure through loss of barrier function. Methods: The renal epithelial cell model, MDCK cells were employed to examine metalloproteinase activity and mRNA expression. Epithelial barrier function was determined using paracellular flux studies. Results: We found that matrix metalloproteinase-9 expression (MMP-9) and activity is markedly elevated in response to tumor necrosis factor-α exposure through a mitogen-activated protein kinase dependent pathway. The MMP-9 is predominately secreted into the apical compartment and elevated MMP-9 expression correlates with impaired cell barrier function that was restored using a specific inhibitor of MMP activity. Addition of recombinant MMP-9 to the apical compartment of MDCK cultures significantly elevated paracellular flux rate. Conclusions: We provide direct evidence for a MMP-9-mediated mechanism that produces junctional disruption. Collectively, these findings support the hypothesis that impaired epithelial barrier function due to activation of tissue/matrix degrading mechanisms occurs in response to specific inflammatory cues.

Original languageEnglish (US)
Pages (from-to)99-112
Number of pages14
JournalCellular Physiology and Biochemistry
Volume19
Issue number1-4
DOIs
StatePublished - 2007
Externally publishedYes

Keywords

  • Epithelial barrier
  • Matrix metalloproteinase
  • MDCK cells
  • MMP-9 gene expression
  • Tumor necrosis factor-α
  • Zymography

ASJC Scopus subject areas

  • Physiology

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