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Clathrin heavy chain is required for TNF-induced inflammatory signaling

Guillermo A Escobar1, Robert C McIntyre, Ernest E Moore

  • 1University of Colorado Health Sciences Center, Denver, CO 80262, USA.

Surgery
|August 15, 2006
PubMed

Insights

Clathrin heavy chain (CHC) is essential for tumor necrosis factor alpha (TNF-alpha)-induced inflammatory signaling, as its knockdown impairs key phosphorylation events and reduces inflammatory marker production.

Area of Science:

  • Cellular Biology
  • Immunology
  • Molecular Signaling

Background:

  • Tumor necrosis factor receptor I (TNFR1) signaling involves recruitment of TRADD and kinases, leading to inhibitor kappa B alpha (IKB alpha) phosphorylation and nuclear factor kappa B (NFKB) activation.
  • Clathrin-mediated endocytosis is often crucial for receptor signaling scaffolds.
  • The role of clathrin heavy chain (CHC) in TNF-alpha-induced inflammatory signaling was investigated.

Purpose of the Study:

  • To determine the role of clathrin heavy chain (CHC) in tumor necrosis factor alpha (TNF-alpha)-induced IKB alpha phosphorylation and NFKB activation.
  • To test the hypothesis that CHC is required for TNF-alpha-induced inflammatory signaling.

Main Methods:

  • Human pulmonary epithelial cells were treated with small interfering RNA (siRNA) to knock down clathrin heavy chain (CHCsil).
  • Cells were exposed to TNF-alpha, and levels of IKB alpha, phosphorylated IKB alpha (p-IKB alpha), and phosphorylated P65 were assessed via immunoblot staining.
  • TNF-alpha-induced release of monocyte chemoattractant protein 1 (MCP-1) was measured using ELISA.

Main Results:

  • TNF-alpha induced IKB alpha phosphorylation and P65 phosphorylation.
  • CHC knockdown significantly diminished p-IKB alpha by 91% and P65 phosphorylation by 66%, while IKB alpha degradation remained unaffected.
  • CHC knockdown decreased TNF-alpha-induced MCP-1 release by 46%.

Conclusions:

  • Clathrin heavy chain (CHC) knockdown significantly impairs TNF-alpha-induced phosphorylation of IKB alpha and P65.
  • CHC knockdown also significantly reduces the production of the inflammatory chemokine MCP-1.
  • These findings indicate that CHC plays a required role in specific TNF-alpha-induced inflammatory signaling pathways.
Abstract

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