Celastrol ameliorates cytokine toxicity and pro-inflammatory immune responses by suppressing NF-κB activation in RINm5F beta cells
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초록
Upregulation of pro-inflammatory mediators contributes to-cell destruction and enhanced infiltration of immune cells intopancreatic islets during development of type 1 diabetesmellitus. In this study, we examined the regulatory effects andthe mechanisms of action of celastrol against cytotoxicity andpro-inflammatory immune responses in the RINm5F rat pancreaticβ-cell line stimulated with a combination of interleukin-1beta, tumor necrosis factor-alpha, and interferon-γ. Celastrolsignificantly restored cytokine-induced cell death and significantlyinhibited cytokine-induced nitric oxide production. Inaddition, the protective effect of celastrol was correlated with areduction in pro-inflammatory mediators, such as inducible nitricoxide synthase, cyclooxygenase-2, and CC chemokine ligand2. Furthermore, celastrol significantly suppressed cytokine-induced signaling cascades leading to nuclear factor kappaB (NF-κB) activation, including IκB-kinase (IKK) activation,IκB degradation, p65 phosphorylation, and p65 DNA bindingactivity. These results suggest that celastrol may exert its cytoprotectiveactivity by suppressing cytokine-induced expressionof pro-inflammatory mediators by inhibiting activation ofNF-κB in RINm5F cells.
Abstract
Upregulation of pro-inflammatory mediators contributes to-cell destruction and enhanced infiltration of immune cells intopancreatic islets during development of type 1 diabetesmellitus. In this study, we examined the regulatory effects andthe mechanisms of action of celastrol against cytotoxicity andpro-inflammatory immune responses in the RINm5F rat pancreaticβ-cell line stimulated with a combination of interleukin-1beta, tumor necrosis factor-alpha, and interferon-γ. Celastrolsignificantly restored cytokine-induced cell death and significantlyinhibited cytokine-induced nitric oxide production. Inaddition, the protective effect of celastrol was correlated with areduction in pro-inflammatory mediators, such as inducible nitricoxide synthase, cyclooxygenase-2, and CC chemokine ligand2. Furthermore, celastrol significantly suppressed cytokine-induced signaling cascades leading to nuclear factor kappaB (NF-κB) activation, including IκB-kinase (IKK) activation,IκB degradation, p65 phosphorylation, and p65 DNA bindingactivity. These results suggest that celastrol may exert its cytoprotectiveactivity by suppressing cytokine-induced expressionof pro-inflammatory mediators by inhibiting activation ofNF-κB in RINm5F cells.
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