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* = Presenting author

P055. HDAC dependent regulation of the IL-6/STAT3 pathway during T helper cell activation

E. Sonnenberg1, R. Glauben1, P. Mascagni2, B. Siegmund1, 1Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Gastroenterologie, Berlin, Germany, 2Italfarmaco, Cinisello, Italy

Background

Histone modifications represent a promising new approach in cases where cell functions are to be modulated as in autoimmune diseases or cancer. While several histone deacetylase (HDAC) inhibitors are currently in clinical cancer studies, we demonstrated an additional anti-inflammatory potency in murine colitis models. Here we describe a possible cellular mechanism for this effect.

Methods

Murine naïve T helper cells were isolated via magnetic cell sorting and macrophages were derived from bone marrow (BMMΦ). T cells were stimulated using coated anti-CD3/CD4 antibodies, macrophages via LPS. Cells were analysed using flow cytometry, cytometric bead array or western blot. Acute DSS colitis was performed.

Results

In the presence of the HDAC Inhibitor, ITF2357, the generation of FoxP3+ cells from naïve T helper cells could be enhanced, the polarization to the pro-inflammatory Th17 cells suppressed. In parallel, we demonstrated a dose-dependent down-regulation of the IL-6 receptor on naïve CD4 T cells treated with ITF2357. This effect could be observed on the mRNA expression level and on the protein level via flow cytometry. These results were confirmed in murine colitis models, where the IL-6R expression was diminished on naïve T cells within the lymphnodes, paralleled by a significant reduction of Th17 cells in the lamina propria of ITF2357-treated animals. Consequently, HDAC inhibition resulted in a reduced amount of activated/phosphorylated STAT3 in T cells identifying the IL-6/STAT3/IL-17 pathway as an important target of HDAC inhibitors.

In parallel, ITF2357 treatment of BMMΦ leads to a dose-dependent down regulation of TNFα, IL-6 and IL-12p70 secretion by BMMΦ. TLR4-dependent IL-6R up regulation was significantly impaired by ITF2357, while expression of the signaling transducer CD130 was unchanged. ITF2357 reduced the ability of antigen-specific, MHC-II-dependent T-cell activation.

Conclusion

The present study demonstrates that inhibition of HDAC exerts an anti-inflammatory potency by modulation in T cell polarization directly, but also via affecting macrophage differentiation, leading to impaired IL-6 signalling, reduced T-cell activation, thus representing a novel therapeutic approach for inflammatory bowel disease.