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

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. B degradation, p65 phosphorylation, and p65 DNA binding activity. These results suggest that celastrol may exert its cyto-protective activity by suppressing cytokine-induced expression of pro-inflammatory mediators by inhibiting activation of NF-kappa B in RINm5F cells.