IGFBP-3 inhibits TNF-α production and TNFR-2 signaling to protect against retinal endothelial cell apoptosis

Microvasc Res. 2014 Sep:95:76-81. doi: 10.1016/j.mvr.2014.07.009. Epub 2014 Jul 30.

Abstract

In models of diabetic retinopathy, insulin-like growth factor binding protein-3 (IGFBP-3) protects against tumor necrosis factors-alpha (TNF-α)-mediated apoptosis of retinal microvascular endothelial cells (REC), but the underlying mechanisms are unclear. Our current findings suggest that at least two discrete but complimentary pathways contribute to the protective effects of IGFBP-3; 1) IGFBP-3 directly activates the c-Jun kinase/tissue inhibitor of metalloproteinase-3/TNF-α converting enzyme (c-Jun/TIMP-3/TACE), pathway, which in turn inhibits TNF-α production; 2) IGFBP-3 acts through the IGFBP-3 receptor, low-density lipoprotein receptor-related protein 1 (LRP1), to inhibit signaling of TNF-α receptor 2 (TNFR2). Combined, these two IGFBP-3 pathways substantially reduce REC apoptosis and offer potential targets for the treatment of diabetic retinopathy.

Keywords: Apoptosis; Diabetic retinopathy; IGFBP-3; TNFalpha; c-Jun.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins / metabolism
  • ADAM17 Protein
  • Apoptosis*
  • Cells, Cultured
  • Diabetic Retinopathy / genetics
  • Diabetic Retinopathy / metabolism*
  • Diabetic Retinopathy / pathology
  • Endothelial Cells / metabolism*
  • Endothelial Cells / pathology
  • Humans
  • Insulin-Like Growth Factor Binding Protein 3 / metabolism*
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Low Density Lipoprotein Receptor-Related Protein-1 / genetics
  • Low Density Lipoprotein Receptor-Related Protein-1 / metabolism
  • Receptors, Tumor Necrosis Factor, Type II / metabolism*
  • Retinal Vessels / metabolism*
  • Retinal Vessels / pathology
  • Signal Transduction*
  • Tissue Inhibitor of Metalloproteinase-3 / metabolism
  • Transfection
  • Tumor Necrosis Factor-alpha / metabolism*

Substances

  • IGFBP3 protein, human
  • Insulin-Like Growth Factor Binding Protein 3
  • LRP1 protein, human
  • Low Density Lipoprotein Receptor-Related Protein-1
  • Receptors, Tumor Necrosis Factor, Type II
  • TIMP3 protein, human
  • TNFRSF1B protein, human
  • Tissue Inhibitor of Metalloproteinase-3
  • Tumor Necrosis Factor-alpha
  • JNK Mitogen-Activated Protein Kinases
  • ADAM Proteins
  • ADAM17 Protein
  • ADAM17 protein, human