title: IGFBP-3 and TNF-α regulate retinal endothelial cell apoptosis.
abstract: OBJECTIVE
  We hypothesized that loss of insulin-like growth factor binding protein 3 (IGFBP-3) signaling would produce neuronal changes in the retina similar to early diabetes.
  
  
  METHODS
  To understand better the role of IGFBP-3 in the retina, IGFBP-3 knockout (KO) mice were evaluated for neuronal, vascular, and functional changes compared to wild-type littermates. We also cultured retinal endothelial cells (REC) in normoglycemia or hyperglycemia to determine the interaction between IGFBP-3 and TNF-α, as data indicate that both proteins are regulated by β-adrenergic receptors and respond antagonistically. We also treated some cells with Compound 49b, a novel β-adrenergic receptor agonist we have reported previously to regulate IGFBP-3 and TNF-α.
  
  
  RESULTS
  Electroretinogram analyses showed decreased B-wave and oscillatory potential amplitudes in the IGFBP-3 KO mice, corresponding to increased apoptosis. Retinal thickness and cell numbers in the ganglion cell layer were reduced in the IGFBP-3 KO mice. As expected, loss of IGFBP-3 was associated with increased TNF-α levels. When TNF-α and IGFBP-3 were applied to REC, they worked antagonistically, with IGFBP-3 inhibiting apoptosis and TNF-α promoting apoptosis. Due to their antagonistic nature, results suggest that apoptosis of REC may depend upon which protein (IGFBP-3 versus TNF-α) is active.
  
  
  CONCLUSIONS
  Taken together, loss of IGFBP-3 signaling results in a phenotype similar to neuronal changes observed in diabetic retinopathy in the early phases, including increased TNF-α levels.
authors.affiliation: Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
authors.forename: Qiuhua
authors.initials: Q
authors.lastname: Zhang
authors.forename: Youde
authors.initials: Y
authors.lastname: Jiang
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Miller
authors.forename: Bonnie
authors.initials: B
authors.lastname: Peng
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.forename: Carl
authors.initials: C
authors.lastname: Soderland
authors.forename: Jie
authors.initials: J
authors.lastname: Tang
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Kern
authors.forename: John
authors.initials: J
authors.lastname: Pintar
authors.forename: Jena J
authors.initials: JJ
authors.lastname: Steinle
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental; D003930:Diabetic Retinopathy / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004596:Electroretinography; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012160:Retina / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D018972:Insulin-Like Growth Factor Binding Protein 3; D014409:Tumor Necrosis Factor-alpha
keywords: IGFBP-3; TNF-α; apoptosis