NF kappa B is a central mediator of inflammation. Present inhibitors of NF kappa B are mostly based on inhibition of essential machinery such as proteasome and protein kinases, or activation of nuclear receptors;as such, they are of limited therapeutic use due to severe toxicity. Here we report an LPS-induced NF kappa B enhanceosome in which TonEBP is required for the recruitment of p300. Increased expression of TonEBP enhances the NF kappa B activity and reduced TonEBP expression lowers it. Recombinant TonEBP molecules incapable of recruiting p300 do not stimulate NF kappa B. Myeloid-specific deletion of TonEBP results in milder inflammation and sepsis. We discover that a natural small molecule cerulenin specifically disrupts the enhanceosome without affecting the activation of NF kappa B itself. Cerulenin suppresses the pro-inflammatory activation of macrophages and sepsis without detectable toxicity. Thus, the NF kappa B enhanceosome offers a promising target for useful anti-inflammatory agents.