Neuroprotective effects of IGF-I against TNFalpha-induced neuronal damage in HIV-associated dementia.
Human immunodeficiency virus type 1 (HIV-1) infection often results in disorders of the central nervous system, including HIV-associated dementia (HAD). It is suspected that tumor necrosis factor-alpha (TNFalpha) released by activated and/or infected macrophages/microglia plays a role in the process of neuronal damage seen in AIDS patients. In light of earlier studies showing that the activation of the insulin-like growth factor I receptor (IGF-IR) exerts a strong neuroprotective effect, we investigated the ability of IGF-I to protect neuronal cells from HIV-infected macrophages. Our results demonstrate that the conditioned medium from HIV-1-infected macrophages, HIV/CM, causes loss of neuronal processes in differentiated PC12 and P19 neurons and that these neurodegenerative effects are associated with the presence of TNFalpha. Furthermore, we demonstrate that IGF-I rescues differentiated neurons from both HIV/CM and TNFalpha-induced damage and that IGF-I-mediated neuroprotection is strongly enhanced by overexpression of the wt IGF-IR cDNA and attenuated by the antisense IGF-IR cDNA. Finally, IGF-I-mediated antiapoptotic pathways are continuously functional in differentiated neurons exposed to HIV/CM and are likely supported by TNFalpha-mediated phosphorylation of I(kappa)B. All together these results suggest that the balance between TNFalpha and IGF-IR signaling pathways may control the extent of neuronal injury in this HIV-related experimental setting.
Ying Wang
Jin
J
Center for Neurovirology and Cancer Biology, College of Science and Technology, Temple University, Philadelphia, Pennsylvania 19122, USA.
Peruzzi
Francesca
F
Lassak
Adam
A
Del Valle
Luis
L
Radhakrishnan
Sujahata
S
Rappaport
Jay
J
Khalili
Kamel
K
Amini
Shohreh
S
Reiss
Krzysztof
K
D015526:AIDS Dementia Complex / Q000473:pathology*; D000818:Animals; D002460:Cell Line; D017077:Culture Media, Conditioned / Q000633:toxicity; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D008264:Macrophages / Q000502:physiology / Q000821:virology; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D018696:Neuroprotective Agents; D051381:Rats; D017526:Receptor, IGF Type 1 / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity*
D017077:Culture Media, Conditioned; D018696:Neuroprotective Agents; D014409:Tumor Necrosis Factor-alpha; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1