Activated glia induce neuron death via MAP kinase signaling pathways involving JNK and p38.
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.
Xie
Zhong
Z
Department of Cell and Molecular Biology, and Drug Discovery Program, Northwestern University Feinberg School of Medicine, 303 E. Chicago Avenue, Chicago, IL 60612, USA.
Smith
Carolyn J
CJ
Van Eldik
Linda J
LJ
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
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