zerumbone and Protein-Aggregation--Pathological

Zerumbone is a sesquiterpene present in Zinger zerumbet. Many studies have demonstrated its marked anti-inflammatory and anti-carcinogenesis activities. Recently, we showed that zerumbone binds to numerous proteins with scant selectivity and induces the expression of heat shock proteins (HSPs) in hepatocytes. To dampen proteo-toxic stress, organisms have a stress-responsive molecular machinery, known as heat shock response. Heat shock factor 1 (HSF1) plays a key role in this protein quality control system by promoting activation of HSPs. In this study, we investigated whether zerumbone-induced HSF1 activation contributes to its anti-inflammatory functions in stimulated macrophages. Our findings showed that zerumbone increased cellular protein aggregates and promoted nuclear translocation of HSF1 for HSP expression. Interestingly, HSF1 down-regulation attenuated the suppressive effects of zerumbone on mRNA and protein expressions of pro-inflammatory genes, including inducible nitric oxide synthase and interlukin-1β. These results suggest that proteo-stress induced by zerumbone activates HSF1 for exhibiting its anti-inflammatory functions.

Topics: Animals; Anti-Inflammatory Agents; Blotting, Western; DNA-Binding Proteins; Enzyme-Linked Immunosorbent Assay; Heat Shock Transcription Factors; HSP72 Heat-Shock Proteins; Interleukin-1beta; Interleukin-6; Mice; Nitric Oxide Synthase Type II; Protein Aggregation, Pathological; RAW 264.7 Cells; Real-Time Polymerase Chain Reaction; RNA Interference; Sesquiterpenes; Transcription Factors; Tumor Necrosis Factor-alpha