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Celastrol ameliorates cytokine toxicity and pro-inflammatory immune responses by suppressing NF-κB activation in RINm5F beta cells

  • Ju, Sung Mi (Department of Biomedical Science and Research Institute for Bioscience & Biotechnology, Hallym University) ;
  • Youn, Gi Soo (Department of Biomedical Science and Research Institute for Bioscience & Biotechnology, Hallym University) ;
  • Cho, Yoon Shin (Department of Biomedical Science and Research Institute for Bioscience & Biotechnology, Hallym University) ;
  • Choi, Soo Young (Department of Biomedical Science and Research Institute for Bioscience & Biotechnology, Hallym University) ;
  • Park, Jinseu (Department of Biomedical Science and Research Institute for Bioscience & Biotechnology, Hallym University)
  • Received : 2014.07.15
  • Accepted : 2014.07.23
  • Published : 2015.03.31

Abstract

Upregulation of pro-inflammatory mediators contributes to ${\beta}$-cell destruction and enhanced infiltration of immune cells into pancreatic islets during development of type 1 diabetes mellitus. In this study, we examined the regulatory effects and the mechanisms of action of celastrol against cytotoxicity and pro-inflammatory immune responses in the RINm5F rat pancreatic ${\beta}$-cell line stimulated with a combination of interleukin-1 beta, tumor necrosis factor-alpha, and interferon-${\gamma}$. Celastrol significantly restored cytokine-induced cell death and significantly inhibited cytokine-induced nitric oxide production. In addition, the protective effect of celastrol was correlated with a reduction in pro-inflammatory mediators, such as inducible nitric oxide synthase, cyclooxygenase-2, and CC chemokine ligand 2. Furthermore, celastrol significantly suppressed cytokine-induced signaling cascades leading to nuclear factor kappa B (NF-${\kappa}B$) activation, including $I{\kappa}B$-kinase (IKK) activation, $I{\kappa}B$ degradation, p65 phosphorylation, and p65 DNA binding activity. These results suggest that celastrol may exert its cytoprotective activity by suppressing cytokine-induced expression of pro-inflammatory mediators by inhibiting activation of NF-${\kappa}B$ in RINm5F cells.

Acknowledgement

Supported by : National Research Foundation of Korea

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