3rd Annual BMRP Investigator Meeting - Abstract

Specific Inhibition of Histone Deacetylases as Novel Anti-inflammatory and Anti-proliferative Approach in Experimental Colitis

Rainer Glauben, Arvind Batra, Inka Fedke, Hans A. Lehr, Paolo Mascagni, Charles A. Dinarello, Martin Zeitz and Britta Siegmund^a

Department of Medicine, Charité Universitatsmedizin Berlin, Campus Benjamin Franklin (Berlin, Germany)

Histone deacetylase inhibitors (HDACi) have been described as inducers of growth arrest and apoptotic cell death and are currently in clinical studies for solid tumors.  Recently, an anti-inflammatory potency was demonstrated for the class I HDACi suberoylanilide hydroxamic acid (SAHA) (PNAS (2001); 99:2995).  Thus, HDACi from different classes were analyzed for their anti-inflammatory and apoptotic effects in vitro using PBMC as well as mouse splenocytes. Independent from the HDACi class, a dose-dependent suppression of pro-inflammatory cytokines was observed associated with an increase in histone 3 acetylation.  These effects were confirmed in vivo using the dextran sulphate sodium (DSS) and the trinitrobenzene sulfonic acid (TNBS) models of experimental colitis.  Here, SAHA and valproic acid (VPA) treatment resulted in a dose-dependent decrease in the severity of colitis, as evaluated macroscopically and histologically.  Furthermore, in the DSS- and TNBS-model, there was a significant suppression of IL-6 and IFNγ in colon culture supernatants as well as in stimulated lamina propria lymphocytes.  In HDACi-treated mice, a dose-dependent increase in histone 3 acetylation was shown at the site of inflammation.  To evaluate the anti-proliferative potency of SAHA and VPA, the azoxymethane (AOM)-DSS-model for inflammation-induced colon carcinogenesis was applied.  Preliminary data indicate that HDACi treatment is associated with a delay in tumor development as evaluated by endoscopy.  In conclusion, inhibition of HDAC provides a new anti-inflammatory and possibly new anti-proliferative therapeutic strategy to be evaluated in human disease.

^aPrincipal Investigator