TIMP3 regulates mammary epithelial apoptosis with immune cell recruitment through differential TNF dependence

PLoS One. 2011;6(10):e26718. doi: 10.1371/journal.pone.0026718. Epub 2011 Oct 28.


Post-lactation mammary involution is a homeostatic process requiring epithelial apoptosis and clearance. Given that the deficiency of the extracellular metalloproteinase inhibitor TIMP3 impacts epithelial apoptosis and heightens inflammatory response, we investigated whether TIMP3 regulates these distinct processes during the phases of mammary gland involution in the mouse. Here we show that TIMP3 deficiency leads to TNF dysregulation, earlier caspase activation and onset of mitochondrial apoptosis. This accelerated first phase of involution includes faster loss of initiating signals (STAT3 activation; TGFβ3) concurrent with immediate luminal deconstruction through E-cadherin fragmentation. Epithelial apoptosis is followed by accelerated adipogenesis and a greater macrophage and T-cell infiltration in Timp3(-/-) involuting glands. Crossing in Tnf deficiency abrogates caspase 3 activation, but heightens macrophage and T-cell influx into Timp3(-/-) glands. The data indicate that TIMP3 differentially impacts apoptosis and inflammatory cell influx, based on involvement of TNF, during the process of mammary involution. An understanding of the molecular factors and wound healing microenvironment of the postpartum mammary gland may have implications for understanding pregnancy-associated breast cancer risk.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adherens Junctions / drug effects
  • Adherens Junctions / metabolism
  • Adipogenesis / drug effects
  • Animals
  • Apoptosis* / drug effects
  • Cadherins / metabolism
  • Caspase 3 / metabolism
  • Cell Survival / drug effects
  • Enzyme Activation / drug effects
  • Epithelial Cells / drug effects
  • Epithelial Cells / enzymology
  • Epithelial Cells / immunology*
  • Epithelial Cells / pathology*
  • Female
  • Humans
  • Inflammation / pathology
  • Lymphocytes / drug effects
  • Lymphocytes / immunology*
  • Mammary Glands, Animal / enzymology
  • Mammary Glands, Animal / growth & development
  • Mammary Glands, Animal / immunology
  • Mammary Glands, Animal / pathology*
  • Mice
  • Mice, Inbred C57BL
  • Models, Biological
  • Recombinant Proteins / pharmacology
  • Signal Transduction / drug effects
  • Tissue Inhibitor of Metalloproteinase-3 / deficiency
  • Tissue Inhibitor of Metalloproteinase-3 / metabolism*
  • Tumor Necrosis Factor-alpha / metabolism*


  • Cadherins
  • Recombinant Proteins
  • Tissue Inhibitor of Metalloproteinase-3
  • Tumor Necrosis Factor-alpha
  • Caspase 3