Lipopolysaccharide-activated SHP-1-deficient motheaten microglia release increased nitric oxide, TNF-alpha, and IL-1beta.
Accumulating evidence suggests a deleterious role for activated microglia in facilitating neuronal death by producing neurocytotoxic substances during injury, infection, or neurodegenerative diseases. After cochlear ablation, abnormal microglial activation accompanied by increased neuronal loss within the auditory brainstem occurs in motheaten (me/me) mice deficient in the protein tyrosine phosphatase SHP-1. To determine whether abnormally activated microglia contribute to neuronal death in me/me mice, primary microglial cultures from me/me and wild-type mouse cortices were stimulated by the bacterial endotoxin lipopolysaccharide (LPS) to evaluate the secretion of the neurotoxic mediators nitric oxide (NO), tumor necrosis factor-alpha (TNF-alpha), and interleukin-1beta (IL-1beta). Me/me microglia release significantly greater amounts of all three mediators compared with wild-type microglia. However, the increased release of these compounds in microglia lacking SHP-1 does not appear to occur through activation of extracellular signal-regulated kinase (ERK), p38 kinase subgroups of mitogen-activated protein (MAP) kinases, or increases in NF-kappaB-inducing kinase (NIK). These results suggest that abnormal microglial activation and release of neurotoxic compounds may potentiate neuronal death in deafferented cells and can thus potentiate neurodegeneration in the me/me brainstem. Our data also indicate that SHP-1 is engaged in signaling pathways in LPS-activated microglia, but not through regulation of the ERK and p38 MAP kinases.
Zhao
Jie
J
Department of Biomedical and Pharmaceutical Sciences, School of Pharmacy and Allied Health Sciences, University of Montana, Missoula, MT 59812, USA.
Brooks
Diane M
DM
Lurie
Diana I
DI
D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D001933:Brain Stem / Q000166:cytology / Q000502:physiology; D016923:Cell Death / Q000502:physiology; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000096:biosynthesis; D005838:Genotype; D007375:Interleukin-1 / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D008809:Mice, Inbred C3H; D008818:Mice, Neurologic Mutants; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D009569:Nitric Oxide / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000172:deficiency*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013268:Stimulation, Chemical; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000096:biosynthesis; D000097782:NF-kappaB-Inducing Kinase
D048049:Extracellular Signal-Regulated MAP Kinases; D007375:Interleukin-1; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D009419:Nerve Tissue Proteins; D009569:Nitric Oxide; D017346:Protein Serine-Threonine Kinases; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D000097782:NF-kappaB-Inducing Kinase; C509248:Ptpn6 protein, mouse