NF-κB as a common signaling pathway in ganglioside-induced autophagic cell death and activation of astrocytes.
We have previously shown that gangliosides induce autophagic cell death of brain astrocytes. As gangliosides are also known to induce inflammatory activation of astrocytes, we hypothesized that a canonical inflammatory signaling pathway NF-κB might be involved in the ganglioside-induced astrocyte cell death and activation. Using cultured mouse astrocytes and C6 rat glioma cell line, we determined the role of NF-κB in autophagic cell death and nitric oxide (NO) production in astrocytes. Gangliosides induced iNOS/GFAP expression and NF-κB activation. IKK inhibitor SC-514 and NF-κB inhibitor PDTC reduced ganglioside-induced astrocyte activation and cell death. Moreover, inhibition of NF-κB pathway also attenuated autophagy of astrocytes. Rho subfamily of small G proteins antagonized the ganglioside-induced astrocyte cell death as well as activation pathways. Taken together, IKK/NF-κB may constitute one of the common signaling pathways in ganglioside-induced astrocyte activation and autophagic cell death, and may play an important role in the ganglioside intracellular signaling that regulates astrocyte physiology and pathology.
Hwang
Jaegyu
J
Department of Pharmacology, Brain Science and Engineering Institute, CMRI, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
Lee
Ho-Jae
HJ
Lee
Won-Ha
WH
Suk
Kyoungho
K
D000577:Amides / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology*; D001921:Brain / Q000166:cytology; D002103:Cadaverine / Q000031:analogs & derivatives / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005732:Gangliosides / Q000494:pharmacology*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008813:Mice, Inbred ICR; D016328:NF-kappa B / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors; D014162:Transfection / Q000379:methods; D019323:omega-N-Methylarginine / Q000494:pharmacology; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D000577:Amides; D004791:Enzyme Inhibitors; D005732:Gangliosides; D005904:Glial Fibrillary Acidic Protein; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009479:Neuropeptides; D009573:Nitrites; D011725:Pyridines; C484602:Rac1 protein, mouse; C108830:Y 27632; D049452:Green Fluorescent Proteins; D019323:omega-N-Methylarginine; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein; C008542:monodansylcadaverine; D002103:Cadaverine