title: Cross-talk between IGF-1 and estrogen receptors attenuates intracellular changes in ventral spinal cord 4.1 motoneuron cells because of interferon-gamma exposure.
abstract: Insulin-like growth factor-1 (IGF-1) is a neuroprotective growth factor that promotes neuronal survival by inhibition of apoptosis. To examine whether IGF-1 exerts cytoprotective effects against extracellular inflammatory stimulation, ventral spinal cord 4.1 (VSC4.1) motoneuron cells were treated with interferon-gamma (IFN-γ). Our data demonstrated apoptotic changes, increased calpain:calpastatin and Bax:Bcl-2 ratios, and expression of apoptosis-related proteases (caspase-3 and -12) in motoneurons rendered by IFN-γ in a dose-dependent manner. Post-treatment with IGF-1 attenuated these changes. In addition, IGF-1 treatment of motoneurons exposed to IFN-γ decreased expression of inflammatory markers (cyclooxygenase-2 and nuclear factor-kappa B:inhibitor of kappa B ratio). Furthermore, IGF-1 attenuated the loss of expression of IGF-1 receptors (IGF-1Rα and IGF-1Rβ) and estrogen receptors (ERα and ERβ) induced by IFN-γ. To determine whether the protective effects of IGF-1 are associated with ERs, ERs antagonist ICI and selective siRNA targeted against ERα and ERβ were used in VSC4.1 motoneurons. Distinctive morphological changes were observed following siRNA knockdown of ERα and ERβ. In particular, apoptotic cell death assessed by TUNEL assay was enhanced in both ERα and ERβ-silenced VSC4.1 motoneurons following IFN-γ and IGF-1 exposure. These results suggest that IGF-1 protects motoneurons from inflammatory insult by a mechanism involving pivotal interactions with ERα and ERβ.
authors.affiliation: Department of Neurosciences, Division of Neurology, College of Health Professions, Medical University of South Carolina, Charleston, South Carolina, USA.
authors.forename: Sookyoung
authors.initials: S
authors.lastname: Park
authors.forename: Kenkichi
authors.initials: K
authors.lastname: Nozaki
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Smith
authors.forename: James S
authors.initials: JS
authors.lastname: Krause
authors.forename: Naren L
authors.initials: NL
authors.lastname: Banik
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002154:Calpain / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism* / Q000494:pharmacology; D007371:Interferon-gamma / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D009046:Motor Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009447:Neuroblastoma; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D020239:Receptor Cross-Talk / Q000187:drug effects / Q000502:physiology*; D013116:Spinal Cord / Q000166:cytology
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D018696:Neuroprotective Agents; D034741:RNA, Small Interfering; D007334:Insulin-Like Growth Factor I; D007371:Interferon-gamma; D002154:Calpain
keywords: IGF-1; IGF-1 receptor; apoptosis; calpain; estrogen receptor