Received for publication February 15, 2007.
Revised April 26, 2007.
Accepted for publication May 2, 2007.

UR-1505, a new salicylate, blocks T cell activation through Nuclear Factor of Activated T cells

Abstract

UR-1505 is a new molecule, chemically related to salicylic acid with immunomodulator properties, currently under clinical development for 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 NF-AT DNA-binding activity. The effects of UR-1505 (0.1-0.3 µM) on T cell proliferation appears to be dependent on the stimulus, since UR-1505 inhibited CD3/CD28-induced T-cell proliferation, increased p27^KIP levels and induces G1/S cell arrest but, interestingly, did not inhibit the JAK/STAT-induced T-cell proliferation. These data suggest that UR-1505 acts by means of a specific mechanism inhibiting T cell activation depending on TCR signalling pathway. Furthermore, the antiproliferative effects of UR-1505 are not 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 IL-5 and IFN- in activated T cells and this effect was produced at transcriptional level. As 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- mRNA expression, UR-1505 specifically inhibited NF-AT DNA binding without effect on NF-B and AP-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. As 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.

Key words: Jak/Stats, AP-1, NFAT, NFkappaB, DNA binding sites