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.
Matsuoka
Hideaki
H
Pharmacology Research Laboratories, Astellas Pharma Inc., 2-1-6 Kashima, Yodogawa-ku, Osaka 532-8514, Japan. hideaki.matsuoka@jp.astellas.com
Fujimura
Takao
T
Mori
Hiroaki
H
Aramori
Ichiro
I
Mutoh
Seitaro
S
D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007376:Interleukin-2 / Q000235:genetics*; D019169:Jurkat Cells; D016328:NF-kappa B / Q000378:metabolism; D010456:Peptides, Cyclic / Q000494:pharmacology*; D011485:Protein Binding; D021122:Protein Subunits; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects*; D015533:Transcriptional Activation / Q000187:drug effects
C474179:FR 235222; D056572:Histone Deacetylase Inhibitors; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D016328:NF-kappa B; D010456:Peptides, Cyclic; D021122:Protein Subunits; D004247:DNA