Celastrol ameliorates cytokine toxicity and pro-inflammatory immune responses by suppressing NF-ÛB activation in RINm5F beta cells
2015
Ju, S.M., Hallym University, Chunchon, Republic of Korea | Youn, G.S., Hallym University, Chunchon, Republic of Korea | Cho, Y.S., Hallym University, Chunchon, Republic of Korea | Choi, S.Y., Hallym University, Chunchon, Republic of Korea | Park, J., Hallym University, Chunchon, Republic of Korea
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-kB) activation, including IkB-kinase (IKK) activation, IkB 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-kB in RINm5F cells.
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