title: IGFBP-3 inhibits TNF-α production and TNFR-2 signaling to protect against retinal endothelial cell apoptosis.
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.
authors.affiliation: Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Qiuhua
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, TN, USA; Department of Anatomy & Neurobiology, University of Tennessee Health Science Center, Memphis, TN, USA; Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN, USA. Electronic address: jsteinl1@uthsc.edu.
authors.forename: Jena J
authors.initials: JJ
authors.lastname: Steinle
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000072198:ADAM17 Protein; D017209:Apoptosis; D002478:Cells, Cultured; D003930:Diabetic Retinopathy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000235:genetics / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism*; D012171:Retinal Vessels / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000378:metabolism; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; C475476:LRP1 protein, human; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D047889:Receptors, Tumor Necrosis Factor, Type II; C088390:TIMP3 protein, human; C415902:TNFRSF1B protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3; D014409:Tumor Necrosis Factor-alpha; D048031:JNK Mitogen-Activated Protein Kinases; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human
keywords: Apoptosis; Diabetic retinopathy; IGFBP-3; TNFalpha; c-Jun
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