Cross-talk between IGF-1 and estrogen receptors attenuates intracellular changes in ventral spinal cord 4.1 motoneuron cells because of interferon-gamma exposure

Authors

  • Sookyoung Park,

    1. Department of Neurosciences, Division of Neurology, College of Health Professions, Medical University of South Carolina, Charleston, South Carolina, USA
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  • Kenkichi Nozaki,

    1. Department of Neurosciences, Division of Neurology, College of Health Professions, Medical University of South Carolina, Charleston, South Carolina, USA
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  • Joshua A. Smith,

    1. Department of Neurosciences, Division of Neurology, College of Health Professions, Medical University of South Carolina, Charleston, South Carolina, USA
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  • James S. Krause,

    1. Department of Health Sciences and Research, College of Health Professions, Medical University of South Carolina, Charleston, South Carolina, USA
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  • Naren L. Banik

    Corresponding author
    1. Department of Neurosciences, Division of Neurology, College of Health Professions, Medical University of South Carolina, Charleston, South Carolina, USA
    • Address correspondence and reprint requests to Naren L. Banik, Division of Neurology, Department of Neurosciences, Medical university of South Carolina, 96 Jonathan Lucas Street, Suite 309 CSB, Charleston, SC 29425, USA. E-mail: baniknl@musc.edu

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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.

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Pro-inflammatory Th1 cytokine, IFN-γ induced cellular damage was investigated in VSC4.1 motoneurons. IFN-γ resulted in apoptosis and inflammatory changes in motoneurons. Apoptosis was mediated via up-regulation of calpain and subsequent cleavage of caspase-3. IGF-1 is suggested as potentially neuroprotective in motoneuron following cytokine exposure. Cellular protective effects of IGF-1 are mediated by cross-talk with ERα and ERβ in VSC4.1 motoneurons.

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