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UR-1505, a New Salicylate, Blocks T Cell Activation through Nuclear Factor of Activated T Cells

2007; American Society for Pharmacology and Experimental Therapeutics; Volume: 72; Issue: 2 Linguagem: Inglês

10.1124/mol.107.035212

1521-0111

Juan Román, Alberto Fernández de Arriba, Sonia Barrón, Pedro Michelena, Marta Giral, Manuel Merlos, Elvira Bailón, Mónica Comalada, Júlio Gálvez, Antonio Zarzuelo, Isabel Ramis,

Macrophage Migration Inhibitory Factor

2-Hydroxy-4(-2,2,3,3,3-pentafluoropropoxy)-benzoic acid (UR-1505), a new molecule chemically related to salicylic acid, has immunomodulator properties and is currently under clinical development for treatment of atopic dermatitis. The present work describes the immunomodulatory profile of UR-1505. UR-1505 targets T cells, inhibiting their proliferation and cytokine production by blocking nuclear factor of activated T cells (NF-AT) DNA-binding activity. The effects of UR-1505 (100-300 μM) on T cell proliferation seems to be dependent on the stimulus, because UR-1505 inhibited CD3/CD28-induced T-cell proliferation, increased p27 KIP levels, and induced G 1 /S cell arrest but, interestingly, did not inhibit the Janus tyrosine kinase/signal transducer and activator of transcription-induced T-cell proliferation. These data suggest that UR-1505 acts by means of a specific mechanism inhibiting T cell activation depending on T cell receptor signaling pathway. Furthermore, the antiproliferative effects of UR-1505 are not a consequence of decreased cell viability. In addition to the inhibition of T-cell proliferation, UR-1505 decreased, in a dose-dependent manner, the production of interleukin (IL)-5 and interferon (IFN)-γ in activated T cells, and this effect was produced at the transcriptional level. Because T-cell proliferation and cytokine production were regulated through NF-AT, we examined the effect of UR-1505 on this transcription factor. According to its effect on IL-5 and IFN-γ mRNA expression, UR-1505 specifically inhibited NF-AT DNA binding without effect on nuclear factor-κB and activator protein-1 activities. The effect of UR-1505 on NF-AT is not attributable to a blockade of nuclear import. In conclusion, UR-1505 is a new immunomodulator agent that specifically inhibits NF-AT activation. Because NF-AT regulates the transcription of most genes involved in lymphocyte activation, its selective inactivation results in both decreased T-cell proliferation and cytokine production.