In the context of inflammation, SIRT2 was shown to directly bind and deacetylate the p65 subunit of NF-kB, a major transcriptional regulator of the inflammatory response. Accordingly, p65 is hyperacetylated in Sirt22/2 mouse embryonic fibroblasts following TNFa stimulation, resulting in NF-kBdependent gene STO-609 acetate activation and increased apoptosis. Furthermore, in vivo experiments show that SIRT2 is an important inhibitor of microglia-mediated inflammation in the brain, and of inflammatory factors leading to arthritis. These discoveries led to the use of SIRT2 as an anti-inflammatory therapeutic target, as was recently demonstrated by using a permeative protein, Pep-1, to transduce SIRT2 into epithelial cells. Transduction of cells with Pep-1-SIRT2 reduced inflammation by attenuating the expression of cytokines and activation of both NFkB and mitogen activated protein kinases. These recent findings prompted us to examine the potential contribution of SIRT2 in the development of IBD. In the present study, we demonstrate that SIRT2 is critical for modulating macrophage polarization and intestinal permeability, thereby inhibiting the development of colitis. More specifically, SIRT2 knockout mice developed more severe colitis when exposed to the chemical colitis inducer, dextran SCH 28080 sulfate sodium. This phenotype appears to be consequent to a hyper-activated immune cell compartment with secondary changes in the intestinal epithelium. SIRT2 belongs to a highly conserved family of NAD + -dependent enzymes, consisting of seven members, which vary in subcellular localizations and have substrates ranging from histones to transcription factors and enzymes. SIRT2 is primarily a cytosolic protein, but can shuttle into the nucleus, thus explaining its ability to deacetylate both cytosolic and nuclear substrates.