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Tumor necrosis factor-alpha induces MMP-9 expression via p42/p44 MAPK, JNK, and nuclear factor-kappaB in A549 cells

Chih-Chung Lin1, Hsiao-Wei Tseng, Hsi-Lung Hsieh

  • 1Department of Anesthetics, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan.

Toxicology and Applied Pharmacology
|March 14, 2008
PubMed

Insights

Tumor necrosis factor-alpha (TNF-alpha) induces matrix metalloproteinase-9 (MMP-9) in lung cells. This study reveals that MAPK and NF-kappaB pathways are crucial for TNF-alpha-driven MMP-9 gene expression.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Matrix metalloproteinases (MMPs), particularly MMP-9, are implicated in airway inflammation.
  • Tumor necrosis factor-alpha (TNF-alpha) is a known inducer of MMP-9.
  • The precise molecular mechanisms of TNF-alpha-induced MMP-9 expression in human A549 cells require elucidation.

Purpose of the Study:

  • To investigate the signaling pathways involved in TNF-alpha-induced MMP-9 production in human A549 cells.
  • To elucidate the roles of MAPKs (ERK, JNK) and NF-kappaB in regulating MMP-9 gene expression.

Main Methods:

  • Western blotting, RT-PCR, ELISA, and zymography to assess MMP-9 levels.
  • Inhibitor treatments (U0126, SP600125, helenalin) and dominant-negative mutants (DeltaERK, DeltaJNK) to probe signaling pathways.
  • Immunofluorescence staining to track NF-kappaB translocation.
  • Luciferase reporter assays to evaluate promoter activity.
  • siRNA-mediated knockdown of specific signaling molecules.

Main Results:

  • TNF-alpha significantly increased MMP-9 protein and mRNA levels in A549 cells.
  • Inhibition of MEK1/2, JNK, and NF-kappaB pathways, as well as knockdown of ERK, JNK, and MEK1, attenuated TNF-alpha-induced MMP-9 production.
  • TNF-alpha stimulated the phosphorylation of p42/p44 MAPK and JNK.
  • TNF-alpha induced IkappaB-alpha degradation and NF-kappaB nuclear translocation, which was blocked by helenalin.
  • Luciferase assays confirmed that MAPKs and NF-kappaB are essential for TNF-alpha-mediated MMP-9 gene transcription.

Conclusions:

  • Phosphorylation of p42/p44 MAPK and JNK, along with NF-kappaB activation, are critical for TNF-alpha-induced MMP-9 gene expression in A549 cells.
  • These findings clarify the molecular mechanisms underlying MMP-9 regulation by TNF-alpha in lung cells.

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