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Interleukin-6 prevents NMDA-induced neuronal death via Gp130 signaling-dependent IP3R inhibition

Ao-Wang Qiu1, Qin Yang2, Song-Tao Yuan2

  • 1Department of Ophthalmology, The First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu Province 210029, China. qinghuailiu@163.com.

Neuro Endocrinology Letters
|January 1, 2014
PubMed
Abstract

Insights

Interleukin-6 (IL-6) protects neurons from N-methyl-D-aspartate (NMDA) induced cell death by inhibiting inositol 1,4,5-trisphosphate receptors (IP3R). This neuroprotection relies on gp130 signaling, not ryanodine receptors (RyR).

Area of Science:

  • Neuroscience
  • Cell Biology
  • Molecular Biology

Background:

  • Neuronal apoptosis and necrosis are critical in neurodegenerative diseases.
  • Interleukin-6 (IL-6) is a cytokine with known neuroprotective roles.
  • Inositol 1,4,5-trisphosphate receptors (IP3R) and ryanodine receptors (RyR) are key regulators of intracellular calcium release.

Purpose of the Study:

  • To investigate the roles of IP3R and RyR in IL-6 mediated neuroprotection against N-methyl-D-aspartate (NMDA) induced cell death.
  • To elucidate the signaling pathways involved in IL-6's protective effects.

Main Methods:

  • Primary cultures of cerebellar granule neurons (CGNs) were treated with IL-6 and then stimulated with NMDA.
  • IP3R and RyR were antagonized using 2-aminoethoxydiphenyl borate (2-APB) and dantrolene (DAN), respectively.
  • Neuronal death was assessed using TUNEL, caspase-3 activity, and annexin V-FITC/PI staining.
  • Expression of IP3R1 and RyR2 was analyzed via Western blot and real-time PCR.

Main Results:

  • IL-6 significantly reduced NMDA-induced neuronal apoptosis and necrosis.
  • The neuroprotective effects of IL-6 were more pronounced with IP3R antagonism (2-APB) than RyR antagonism (DAN).
  • IL-6 downregulated IP3R1 expression but did not affect RyR2 expression.
  • Anti-gp130 monoclonal antibody blocked all IL-6 mediated neuroprotective effects.

Conclusions:

  • IL-6 confers neuroprotection against NMDA-induced cell death by inhibiting IP3R activity and expression, not RyR.
  • gp130 signaling downstream of the IL-6 receptor mediates this neuroprotective effect.
  • These findings highlight IP3R as a therapeutic target for neuroprotection.

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