title: Signal transduction pathways in mouse microglia N-11 cells activated by advanced glycation endproducts (AGEs).
abstract: Deposition of cross-linked insoluble protein aggregates such as amyloid plaques is characteristic for Alzheimer's disease. Microglial activation by these extracullar deposits has been proposed to play a crucial role in functional degeneration as well as cell death of neurones. A sugar-derived post-translational modification of long-lived proteins, advanced glycation endproducts (AGEs), activate specific signal transduction pathways, resulting in the up-regulation of various pro-inflammatory signals such as cytokines [interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-alpha)] and inducible nitric oxide synthase (iNOS). Our goal was to study AGE-activated signal transduction pathways involved in the induction of pro-inflammatory effectors in the murine microglial cell line N-11. Chicken egg albumin-AGE (CEA-AGE), used as model AGE, induces nitric oxide (NO), TNF-alpha and IL-6 production. The AGE receptor, RAGE, and the transcription factor, nuclear factor kappa B (NF-kappaB), appear to be involved in all pathways, since a neutralizing RAGE antibody and a peptide inhibiting NF-kappaB translocation down-regulated NO, TNF-alpha and IL-6 production. NO and TNF-alpha, but not IL-6 production appear to be regulated independently, since NOS inhibitors did not decrease TNF-alpha secretion and a neutralizing TNF-alpha antibody did not reduce NO production, while employment of NOS inhibitors reduced significantly the secretion of IL-6. Inhibition of the MAP-kinase-kinase (MEK) and phosphatidylinositol 3-kinase (PI3K) pathway, but not that of mitogen-activated protein kinase-p38 (MAPK-p38), reduced NO, TNF-alpha and IL-6 significantly, suggesting that simultaneous activation of the first two pathways is necessary for the AGE-induced induction of these pro-inflammatory stimuli.
authors.affiliation: Neuroimmunological Cell Biology Unit, Interdisciplinary Center of Clinical Research (IZKF), Leipzig, Germany.
authors.forename: Sladjana
authors.initials: S
authors.lastname: Dukic-Stefanovic
authors.forename: Jovana
authors.initials: J
authors.lastname: Gasic-Milenkovic
authors.forename: Winnie
authors.initials: W
authors.lastname: Deuther-Conrad
authors.forename: Gerald
authors.initials: G
authors.lastname: Münch
mesh_terms: D000418:Albumins / Q000737:chemistry; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000737:chemistry; D017127:Glycation End Products, Advanced / Q000138:chemical synthesis / Q000494:pharmacology*; D015850:Interleukin-6 / Q000096:biosynthesis; D051379:Mice; D017628:Microglia / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D000418:Albumins; D000906:Antibodies; D004791:Enzyme Inhibitors; D017127:Glycation End Products, Advanced; D015850:Interleukin-6; D016328:NF-kappa B; D000081082:Phosphoinositide-3 Kinase Inhibitors; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D011505:Protein-Tyrosine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D005947:Glucose