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P21 regulates TGF-beta1-induced pulmonary responses via a TNF-alpha-signaling pathway

Masashi Yamasaki1, Hye-Ryun Kang, Robert J Homer

  • 1Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, Department of Internal Medicine, 300 Cedar Street - S425A TAC, P.O. Box 208057, New Haven, CT 06520-8057, USA.

American Journal of Respiratory Cell and Molecular Biology
|October 13, 2007
PubMed

Insights

Transforming growth factor-beta(1) (TGF-β1) in the lung stimulates p21 expression. The absence of p21 exacerbates TGF-β1-induced lung injury, apoptosis, and fibrosis via TNF-α signaling.

Area of Science:

  • Pulmonary Medicine
  • Cell Biology
  • Immunology

Background:

  • Transforming growth factor-beta(1) (TGF-β1) is a key cytokine in lung injury and repair.
  • Overexpression of TGF-β1 in murine lungs induces apoptosis, fibrosis, inflammation, and destruction.
  • Cyclin-dependent kinase inhibitor p21 is a critical regulator of apoptosis.

Purpose of the Study:

  • To investigate the role of p21 in TGF-β1-induced lung pathogenesis.
  • To determine if TGF-β1 affects p21 expression in the lung.
  • To analyze the impact of p21 deficiency on TGF-β1-mediated lung responses.

Main Methods:

  • Evaluating TGF-β1's effect on p21 expression in murine lungs.
  • Comparing transgenic TGF-β1 effects in wild-type and p21 null mutant mice.
  • Analyzing apoptosis, caspase-3 activation, and TNF-α signaling pathways.

Main Results:

  • TGF-β1 significantly increases p21 expression in lung epithelial cells and macrophages.
  • Absence of p21 amplifies TGF-β1-induced lung inflammation, fibrosis, myofibroblast accumulation, and alveolar destruction.
  • TGF-β1 induces p21 via TNF-α signaling, and p21 negatively modulates TGF-β1-induced TNF-α expression.

Conclusions:

  • p21 is a crucial regulator of TGF-β1-induced lung injury.
  • p21 mitigates TGF-β1-driven apoptosis, inflammation, and fibrosis.
  • The interplay between p21 and TNF-α signaling is central to TGF-β1's effects on lung remodeling.

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