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Myeloid, but not pancreatic, RelA/p65 is required for fibrosis in a mouse model of chronic pancreatitis

  • 0II. Medizinische Klinik, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
Gastroenterology +

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July 19, 2011

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July 19, 2011

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View abstract on PubMed

Summary

This summary is machine-generated.

Nuclear factor-kappa B (NF-κB) component RelA/p65 promotes chronic pancreatitis (CP) fibrogenesis in myeloid cells. However, it protects acinar cells from inflammation, with MMP-10 acting as an antifibrogenic factor in macrophages during CP progression.

Area Of Science

  • Molecular Biology
  • Immunology
  • Gastroenterology

Background

  • The role of transcription factors in chronic pancreatitis (CP) pathogenesis is largely unknown.
  • Nuclear factor-kappa B (NF-κB) is a key transcription factor involved in inflammation and immunity.

Purpose Of The Study

  • To investigate the in vivo role of RelA/p65, a subunit of NF-κB, in the pathogenesis of CP.
  • To determine the cell-specific functions of RelA/p65 in CP development.

Main Methods

  • Mice with cell-specific inactivation of RelA/p65 in pancreatic and/or myeloid cells were used.
  • Chronic pancreatitis was induced by repetitive cerulein injections.
  • Histological, biochemical, and gene expression analyses were performed.
  • In vitro co-culture assays and analysis of human CP tissues were conducted.

Main Results

  • RelA/p65 inactivation in the pancreas led to CP development, with increased macrophages and activated pancreatic stellate cells (PSCs).
  • Simultaneous inactivation of RelA/p65 in myeloid cells attenuated fibrosis.
  • RelA/p65-deficient macrophages degraded fibronectin in PSCs.
  • Matrix metalloproteinase (MMP)-10 was identified as a RelA/p65-dependent factor involved in fibronectin degradation.

Conclusions

  • RelA/p65 in myeloid cells promotes CP pathogenesis and fibrogenesis.
  • RelA/p65 in acinar cells protects against chronic inflammation.
  • MMP-10 acts as a potentially antifibrogenic factor in macrophages during CP progression.

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