title: TNFα inhibits IGFBP-3 through activation of p38α and casein kinase 2 in human retinal endothelial cells.
abstract: We recently reported a reciprocal relationship between tumor necrosis factor alpha (TNFα) and insulin-like receptor growth factor binding protein 3 (IGFBP-3) in whole retina of normal and IGFBP-3 knockout mice. A similar relationship was also observed in cultured retinal endothelial cells (REC). We found that TNFα significantly reduced IGFBP-3 levels and vice-versa, IGFBP-3 can lower TNFα and TNFα receptor expression. Since IGFBP-3 is protective to the diabetic retina and TNFα is causative in the development of diabetic retinopathy, we wanted to better understand the cellular mechanisms by which TNFα can reduce IGFBP-3 levels. For these studies, primary human retinal endothelial cells (REC) were used since these cells undergo TNFα-mediated apoptosis under conditions of high glucose conditions and contribute to diabetic retinopathy. We first cultured REC in normal or high glucose, treated with exogenous TNFα, then measured changes in potential signaling pathways, with a focus on P38 mitogen-activated protein kinase alpha (P38α) and casein kinase 2 (CK2) as these pathways have been linked to both TNFα and IGFBP-3. We found that TNFα significantly increased phosphorylation of P38α and CK2. Furthermore, specific inhibitors of P38α or CK2 blocked TNFα inhibition of IGFBP-3 expression, demonstrating that TNFα reduces IGFBP-3 through activation of P38α and CK2. Since TNFα and IGFBP-3 are key mediators of retinal damage and protection respectively in diabetic retinopathy, increased understanding of the relationship between these two proteins will offer new therapeutic options for treatment.
authors: Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
authors: Qiuhua
authors: Q
authors: Zhang
authors: Cell Systems Corp, Kirkland, Washington, United States of America.
authors: Dylan
authors: D
authors: Soderland
authors: Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America; Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America; Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.
authors: Jena J
authors: JJ
authors: Steinle
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D047390:Casein Kinase II / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002478:Cells, Cultured; D003930:Diabetic Retinopathy / Q000473:pathology; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D048308:Mitogen-Activated Protein Kinase 14 / Q000737:chemistry / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation / Q000187:drug effects; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D012160:Retina / Q000166:cytology*; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D018972:Insulin-Like Growth Factor Binding Protein 3; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D047390:Casein Kinase II; D048308:Mitogen-Activated Protein Kinase 14; D005947:Glucose