title: Activated glia induce neuron death via MAP kinase signaling pathways involving JNK and p38.
abstract: Chronic glial activation in neurodegenerative diseases contributes to neuronal dysfunction and neuron loss through production of neuroinflammatory molecules. However, the molecular mechanisms, particularly the signal transduction pathways involved in glia-dependent neuron death, are poorly understood. As a first step to address this question, we used a neuron-glia co-culture system that allows diffusion of soluble molecules between glia and neurons to test the potential importance of mitogen-activated protein kinase (MAPK) signaling pathways in the glia-induced neuron death. Activation of glia in co-culture by lipopolysaccharide (LPS) induced apoptotic-like neuron death. The MAPKs tested (p38, JNK, ERK1/2) were activated in both glia and neurons following LPS treatment, suggesting their involvement in both glial activation and neuronal response to diffusible, glia-derived neurotoxic molecules. Inhibitors of p38 and JNK partially blocked neuron death in the LPS-treated co-culture, whereas an ERK1/2 pathway inhibitor did not protect neurons. These results show that p38 and JNK MAPKs, but not ERK1/2 MAPK, are important signal transduction pathways contributing to glia-induced neuron death.
authors.affiliation: Department of Cell and Molecular Biology, and Drug Discovery Program, Northwestern University Feinberg School of Medicine, 303 E. Chicago Avenue, Chicago, IL 60612, USA.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Xie
authors.forename: Carolyn J
authors.initials: CJ
authors.lastname: Smith
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Van Eldik
mesh_terms: D000818:Animals; D002450:Cell Communication / Q000502:physiology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D018920:Coculture Techniques; D004660:Encephalitis / Q000201:enzymology / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005333:Fetus; D005456:Fluorescent Dyes; D005911:Gliosis / Q000201:enzymology / Q000503:physiopathology; D007372:Interferons / Q000494:pharmacology; D007375:Interleukin-1 / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases; D008070:Lipopolysaccharides / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000201:enzymology; D008928:Mitochondria / Q000201:enzymology / Q000473:pathology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000201:enzymology* / Q000503:physiopathology; D009457:Neuroglia / Q000201:enzymology* / Q000473:pathology; D009474:Neurons / Q000201:enzymology* / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; D007375:Interleukin-1; D008070:Lipopolysaccharides; D007372:Interferons; D019001:Nitric Oxide Synthase; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases