DNA demethylation of the IFNγ locus attenuates experimentally induced asthma

Background: Polarization of T cells towards a Th2 cell based immune reaction is one of the key events in the development of allergic asthma. During the polarization process the Th-1 cytokine IFNγ is silenced by epigenetic mechanisms like de novo DNA methylation while Th2 cytokines are up regulated.

Method: In order to show that epigenetic regulation by DNA methylation is essential for Th1 versus Th2 cell polarization and for the development of an asthmatic phenotype, the DNA methylation at the IFNγ- and the Th2 cytokine locus after the induction of experimental asthma was measured. Mice were treated with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5-aza-2') to test the influence of DNA methylation on the asthmatic phenotype of OVA sensitized and challenged Balb/c mice.

Results: Significantly increased DNA methylation was observed at all analysed CpGs of the IFNγ locus specifically in CD4+ cells after sensitization. Treatment of mice with 5-aza-2' inhibits the DNA methylation at the IFNγ locus in CD4+ cells. Additionally, the number of Foxp3 cells is slightly increasing after 5-aza-2' treatment. The phenotype of experimentally induced asthma improves significantly due to the treatment.

Conclusions: DNA methylation has a crucial role in asthma development in mice due to the regulation of the Th1 cytokine IFNγ. The DNA methyltransferase inhibitor 5-aza-2' interferes with DNA methylation and Th2 cell polarization and is able to attenuate experimentally induced asthma in mice.