Nuclear factor kappa beta (NF-κB) is tightly regulated by multiple checks and balances in order to prevent persistent NF-κB activation that could have deleterious effects on the host. Activation of NF-κB-regulated gene expression is modulated by post-transcriptional modifications, such as phosphorylation, degradative and regulatory ubiquitination, acetylation and methylation, which can be altered upon stimulation. The ubiquitin-proteasome system is the main selective intracellular degradation pathway of unneeded or damaged protein in all eukaryotic cells. Inhibitor of nuclear factor κBα (IκBα) is important proteasome substrate. It is an inhibitor of NF-κB that binds to the nuclear localization domain of transcription factor, preventing it from translocating to the nucleus and promoting target gene expression of NF-κB. Proteasomal degradation of IκBα is required for NF-κB activation. Of particular interest is the acetylation of p65/RelA, a subunit of the heterodimeric NF-κB protein, which can either potentiate or diminish NF-κB signaling depending on the particular acetylated lysine residue. Acetylation of lysine 310 is critical for full activation of NF-κB transcription potential, which can be deacetylated by sirtuin1. In this study, we used Angiostrongylus cantonensis induced-meningitis or meningoencephalitis as a model to investigate whether proteasome, sirtuin1 and PPARγ play important roles in the regulation of NF-κB signaling and proinflammatory gene expression. The first year will use sirtuin1 agnoist resveratrol to detect the changes of sirtuin1 during A. cantonensis infection. Further, to examine the changes of cytokines (IL-1β、IL-5、TNF-α), chemokines (CCL-11) and adhesion molecules (ICAM-1) after resveratrol treatment in A. cantonensis-infected mice.
