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Lipopolysaccharide‐activated SHP‐1‐deficient motheaten microglia release increased nitric oxide, TNF‐α, and IL‐1β
Author(s) -
Zhao Jie,
Brooks Diane M.,
Lurie Diana I.
Publication year - 2006
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.20283
Subject(s) - microglia , biology , mapk/erk pathway , p38 mitogen activated protein kinases , microbiology and biotechnology , kinase , nitric oxide , tumor necrosis factor alpha , neurotoxicity , neuroglia , mitogen activated protein kinase , lipopolysaccharide , neurodegeneration , inflammation , neuroscience , immunology , endocrinology , medicine , central nervous system , disease , toxicity
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‐α (TNF‐α), and interleukin‐1β (IL‐1β). 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‐κB‐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. © 2005 Wiley‐Liss, Inc.