Differential regulation of high glucose-induced glyceraldehyde-3-phosphate dehydrogenase nuclear accumulation in müller cells by IL-1β and IL-6

E. Chepchumba K. Yego, Jason A. Vincent, Vijay Sarthy, Julia V. Busik, Susanne Mohr*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

Abstract

Purpose: This study determined the role of the proinflammatory cytokines known to be elevated in the diabetic retina, namely IL-1β, TNFα, and IL-6, in a high glucose-induced nuclear accumulation of GAPDH in retinal Müller cells, an event considered crucial for the induction of cell death. Methods: With use of the transformed rat Müller cell line (rMC-1) and isolated human Müller cells (HMCs), the authors examined the effect of high glucose (25 mM), IL-1β, TNFα, IL-6, and high glucose (25 mM) plus inhibitors of the caspase-1/IL-1β signaling pathway on GAPDH nuclear accumulation, which was evaluated by immunofluorescence analysis. Results: High glucose induced IL-1β, weak IL-6, and no TNFα production by rMC-1 and HMCs. IL-1β (1-10 ng/mL) significantly increased GAPDH nuclear accumulation in Müller cells in a concentration-dependent manner within 24 hours. Further, high glucose-induced GAPDH nuclear accumulation in Müller cells was mediated by IL-1β. Inhibition of the IL-1 receptor using an IL-1 receptor antagonist (IL-1ra; 50 ng/mL) or inhibition of IL-1β production using a specific caspase-1 inhibitor (YVAD-fmk; 100 μM) significantly decreased high glucose-induced GAPDH nuclear accumulation. In contrast, IL-6 (2 ng/mL) had a strong protective effect attenuating high glucose and IL-1β -induced GAPDH nuclear accumulation in Müller cells. TNFα (1-10 ng/mL) did not have any effect on GAPDH nuclear accumulation. Conclusions: These results revealed a novel mechanism for high glucose-induced GAPDH nuclear accumulation in Müller cells through production and autocrine stimulation by IL-1β The protective role of IL-6 in high glucose- and IL-1β-induced toxicity indicates that changes in the balance of these cytokines might contribute to cellular damage mediated by elevated glucose levels.

Original languageEnglish (US)
Pages (from-to)1920-1928
Number of pages9
JournalInvestigative Ophthalmology and Visual Science
Volume50
Issue number4
DOIs
StatePublished - Apr 2009

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

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