Expression of the p75 TNF receptor is linked to TNF-induced NFkappaB translocation and oxyradical neutralization in glial cells.
Tumor necrosis factor (TNF)-family cytokines induce reactive oxygen species (ROS) that injure vulnerable populations of brain cells. Among glia, oligodendrocytes are particularly susceptible to TNF-induced ROS whereas microglia are protected. We previously found that oligodendrocytes in vitro predominantly express the p55 type-1 TNF receptor, while microglial cells express both type-1 and p75 type-2 receptors. We hypothesized that differential TNF receptor expression and attendant signaling underlies the relative vulnerability of oligodendrocytes, versus microglia, to TNF-induced injury. To test this hypothesis, purified cultures of glial cells were incubated 0-48 hr with TNFalpha or lymphotoxin-alpha, following which levels of ROS, glutathione (GSH), nuclear factor kappa-B (NFkappaB) translocation, and anti-oxidant proteins and activity were measured. 48 hr exposure to TNF increased ROS levels 28% and decreased GSH levels 17% in oligodendrocytes, but decreased levels ROS levels 24% and increased GSH levels 112% increase in microglia. Thirty to 180 min exposure to TNF increased NFkappaB nuclear translocation to a greater extent and for a longer time in microglia versus oligodendrocytes, and this was followed 24-48 hr later with 3- to 13-fold increases in microglia manganese superoxide dismutase protein levels and 6-fold increases in enzyme activity. Collectively, these data suggest that signals transduced through the p75 receptor activate anti-oxidant mechanisms that protect microglia from TNF-induced injury. Lacking such signals, oligodendrocytes are considerably more vulnerable to the injurious effects of TNF.
Dopp
Joel M
JM
Mental Retardation Research Center, University of California at Los Angeles, Los Angeles, California, 90024-1759, USA.
Sarafian
Theodore A
TA
Spinella
Francesca M
FM
Kahn
Michelle A
MA
Shau
Hungyi
H
de Vellis
Jean
J
D000818:Animals; D015152:Blotting, Northern; D007150:Immunohistochemistry; D016328:NF-kappa B / Q000378:metabolism*; D009457:Neuroglia / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D021381:Protein Transport; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D016328:NF-kappa B; D017382:Reactive Oxygen Species; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D013482:Superoxide Dismutase