Oxidative stress is a characteristic of chronic inflammatory diseases. The reactive oxygen intermediate hydrogen peroxide (H2O2) is an important signaling molecule that modulates gene expression. We have demonstrated that H2O2 significantly enhanced cytokine production in BEAS-2B cells, with a maximal effect at 4 h. This did not result from enhanced NF-kappaB activation, but through decreased activity of histone deacetylase (HDAC)2. This results in increased inflammatory gene expression following acetylation of specific histone residues. Decreased HDAC2 activity was associated with tyrosine nitration status. Peroxynitrite and SIN-1, a peroxynitrite generator, were also able to reduce HDAC2 activity via tyrosine nitration. Our data suggest that oxidative stress contributes to worsening inflammation via reduction of HDAC2 activity through HDAC2 nitration. This novel mechanism of inflammation may be important in increasing the severity and chronicity of inflammatory diseases. (C) 2004 Elsevier Inc. All rights reserved.