Involvement of alpha1beta1 integrin in insulin-like growth factor-1-mediated protection of PC12 neuronal processes from tumor necrosis factor-alpha-induced injury.
Insulin-like growth factor 1 receptor (IGF-1R) supports neuronal survival against a wide variety of insults. This includes tumor necrosis factor-alpha (TNFalpha)-mediated neuronal damage, which represents one of the factors suspected to play a role in HIV-associated dementia (HAD). PC12 neurons engineered to express human IGF-1R (PC12/IGF-1R) maintain neuronal processes on collagen IV for several weeks. However, prolonged treatment with TNFalpha caused degeneration of neuronal processes, with no apparent signs of apoptosis. In this process, TNFalpha did not affect IGF-1-mediated phosphorylation of IRS-1, IRS-2, Akt, or Erks. In addition, PC12/IGF-1R cells were found to express predominantly alpha1beta1 integrin, which has high affinity to collagen IV. The treatment of PC12/IGF-1R neurons with a specific alpha1beta1 integrin inhibitor, obtustatin, also caused loss of neuronal processes, accompanied by a quick cell detachment and extensive apoptosis. In the presence of IGF-1, both TNFalpha-induced and obtustatin-induced degeneration of neuronal processes were effectively inhibited. Furthermore, TNFalpha-mediated neuronal degeneration correlated with decreased attachment of PC12/IGF-1R cells to collagen IV and with a reduced level of alpha1beta1 integrin, consistent with a role for this surface protein in the maintenance of neuronal processes. Thus the neuroprotective effects of IGF-1 are not restricted to its antiapoptotic properties but also involve an additional neuroprotective mechanism, by which IGF-1 counteracts the negative effect of TNFalpha on alpha1beta1 integrin-mediated attachment to collagen IV.
Wang
Jin Ying
JY
Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, Philadelphia, Pennsylvania 19122, USA.
Grabacka
Maja
M
Marcinkiewicz
Cezary
C
Staniszewska
Izabella
I
Peruzzi
Francesca
F
Khalili
Kamel
K
Amini
Shohreh
S
Reiss
Krzysztof
K
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002448:Cell Adhesion; D002454:Cell Differentiation / Q000187:drug effects; D019483:Disintegrins / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D047468:Immunoprecipitation; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D039222:Integrin alpha1beta1 / Q000502:physiology*; D016716:PC12 Cells; D010766:Phosphorylation; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000633:toxicity
D000970:Antineoplastic Agents; D019483:Disintegrins; D039222:Integrin alpha1beta1; D010975:Platelet Aggregation Inhibitors; D014409:Tumor Necrosis Factor-alpha; D007334:Insulin-Like Growth Factor I