Tumor necrosis factor alpha is toxic to embryonic mesencephalic dopamine neurons.
Levels of the proinflammatory cytokine tumor necrosis factor alpha (TNFalpha) are increased in postmortem brain and cerebral spinal fluid from patients with Parkinson's disease (PD). This observation provides a basis for associating TNFalpha with neurodegeneration, but a specific toxicity in dopamine (DA) neurons has not been firmly established. Therefore, we investigated TNFalpha-induced toxicity in DA neurons by utilizing primary cultures of embryonic rat mesencephalon. Exposure to TNFalpha resulted in a dose-dependent decrease in DA neurons as evidenced by decreased numbers of tyrosine hydroxylase-immunoreactive (THir) cells. TNFalpha toxicity was selective for DA neurons in that neither glial cell counts nor the total number of neurons was decreased and no general cytotoxicity was evidenced by lactate dehydrogenase assay. Many of the cells which remained immunoreactive for TH had shrunken and rounded cell bodies with broken, blunted, or absent processes. However, TNFalpha-treated cultures also contained some THir cells which appeared to be undamaged and possibly resistant to TNFalpha-induced toxicity. Additionally, immunocytochemistry revealed basal expression of TNFalpha receptor 1 (p55, R1) and TNFalpha receptor 2 (p75, R2) on all cells within the mesencephalic cultures to some degree, even though only DA neurons were affected by TNFalpha treatment. These data strongly suggest that TNFalpha mediates cell death in a sensitive population of DA neurons and support the potential involvement of proinflammatory cytokines in the degeneration of DA neurons in PD.
McGuire
S O
SO
Department of Pharmacology, Rush Presbyterian St. Luke's Medical Center, Chicago, IL 60612, USA.
Ling
Z D
ZD
Lipton
J W
JW
Sortwell
C E
CE
Collier
T J
TJ
Carvey
P M
PM
D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D002455:Cell Division / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000648:ultrastructure; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004298:Dopamine / Q000502:physiology*; D004622:Embryo, Mammalian; D006801:Humans; D007150:Immunohistochemistry; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D008636:Mesencephalon / Q000166:cytology / Q000196:embryology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018124:Receptors, Tumor Necrosis Factor / Q000032:analysis; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D011994:Recombinant Proteins / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity*; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis
D015703:Antigens, CD; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D007770:L-Lactate Dehydrogenase; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine