title: Advanced glycation end products (AGEs) induce apoptosis via a novel pathway: involvement of Ca2+ mediated by interleukin-8 protein.
abstract: Advanced glycation end products (AGEs) accumulate in diabetic patients due to high blood glucose levels and cause multiple deleterious effects. In this study, we provide evidence that the AGE increased cell death, one such deleterious effect. Methyl glyoxal-coupled human serum albumin (AGE-HSA) induced transcription factors such as NF-κB, NF-AT, and AP-1. AGE acts through its cell surface receptor, RAGE, and degranulates vesicular contents including interleukin-8 (IL-8). The number of RAGEs, as well as the amount of NF-κB activation, is low, but the cell death is higher in neuronal cells upon AGE treatment. Degranulated IL-8 acts through its receptors, IL-8Rs, and induces sequential events in cells: increase in intracellular Ca(2+), activation of calcineurin, dephosphorylation of cytoplasmic NF-AT, nuclear translocation of NF-AT, and expression of FasL. Expressed FasL increases activity of caspases and induces cell death. Although AGE increases the amount of reactive oxygen intermediate, accompanying cell death is not dependent upon reactive oxygen intermediate. AGE induces autophagy, which partially protects cells from cell death. A novel mechanism of AGE-mediated cell death in different cell types, especially in neuronal cells where it is an early event, is provided here. Thus, this study may be important in several age-related neuronal diseases where AGE-induced apoptosis is observed because of high amounts of AGE.
authors.affiliation: Laboratory of Immunology, Centre for DNA Fingerprinting and Diagnostics, Nampally, Hyderabad 500 001, India.
authors.forename: Sidharth
authors.initials: S
authors.lastname: Mahali
authors.forename: Nune
authors.initials: N
authors.lastname: Raviprakash
authors.forename: Pongali B
authors.initials: PB
authors.lastname: Raghavendra
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Manna
mesh_terms: D021581:Active Transport, Cell Nucleus; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis; D001343:Autophagy; D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D045744:Cell Line, Tumor; D018925:Chemokines / Q000378:metabolism; D053222:Fas Ligand Protein / Q000378:metabolism; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D017382:Reactive Oxygen Species; D020298:U937 Cells
chemical_list: D000975:Antioxidants; D018925:Chemokines; D053222:Fas Ligand Protein; D017127:Glycation End Products, Advanced; D016209:Interleukin-8; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D019703:Calcineurin; D002118:Calcium