Mechanism of HDAC inhibitor FR235222-mediated IL-2 transcriptional repression in Jurkat cells.

Interleukin (IL)-2 is an essential cytokine in T cell proliferation and homeostasis. The importance of IL-2 down-regulation in preventing acute rejection in organ transplantation and the development of autoimmune diseases has been demonstrated by the therapeutic usefulness of the widely used immunosuppressants cyclosporine A and FK506. Recently, a histone deacetylase (HDAC) inhibitor, FR235222, has been shown to inhibit IL-2 gene expression and to possess immunosuppressive activity in vivo. To elucidate the inhibitory mechanism of FR235222 in IL-2 gene expression, we performed Affymetrix GeneChip analysis of activated Jurkat cells treated with or without FR235222. Here, we show that many NF-kappaB-regulated genes are transcriptionally down-regulated by FR235222 in activated Jurkat cells. Further, luciferase reporter assays revealed that FR235222 selectively inhibits NF-kappaB activity without impairing NF-AT or AP-1 at the concentrations at which it potently inhibits IL-2 promoter activation. These results indicate that FR235222 inhibits IL-2 gene expression via a different mechanism to CsA and FK506, and that FR235222 has the ability to inhibit NF-kappaB activity, which may be partly related to the potent inhibition of IL-2 gene expression by FR235222. Our findings may help our understanding of the molecular mechanism of the inhibition of IL-2 gene expression by HDAC inhibitors and provide insight into the development of more effective and safer new immunosuppressants.