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

Abstract

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 M) on T cell proliferation seems to be dependent on the stimulus, because UR-1505 inhibited CD3/CD28-induced Tcell 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)-␥ 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-␥ mRNA expression, UR-1505 specifically inhibited NF-AT DNA binding without effect on nuclear factor-B 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.

Cyclooxygenase-independent inhibitory effects on T cell activation of novel 4,5-dihydro-3 trifluoromethyl pyrazole cyclooxygenase-2 inhibitors

“…These effects were attributed to the inhibitory effect of these NSAIDs on p38MAPK activation. More recently, salicylates have been shown to inhibit T cell cytokine transcription by a mechanism involving interference on NFAT intrinsic transactivation and DNA binding but not nuclear translocation [59,60].…”

The New Salicylate Derivative UR-1505 Modulates the Th2/Humoral Response in a Dextran Sodium Sulphate Model of Colitis That Resembles Ulcerative Colitis

“…The intestinal anti-inflammatory effects of UR-1505 have been supported by our in vitro results demonstrating the specificity of UR-1505 towards T-cell activity, without affecting macrophage activation (2,4,5). However, in those previous studies, we only focused in the Th1- † Both authors contributed equally to the supervision of the study.…”

UR-1505, a salicylate able to selectively block T-cell activation, shows intestinal anti-inflammatory activity in the chronic phase of the DSS model of rat colitis

“…8,9 Many of the significant advances in the understanding of the etiology of IBD have been derived from the use of experimental models in laboratory animals, thus allowing experiments that are not feasible in humans as well as the study of inflammation over time. Most of the experimental models promote differential activation of T helper 1-type cells, and among them, the DSS- Table 1.…”

“…Among NSAIDs, acetylsalicylic acid is reported to block T-cell activation, 6,7 although this effect was observed at relatively high concentrations. UR-1505 is a novel salicylate derivative compound that has been shown to selectively inhibit T-cell proliferation, to down-regulate T-cell activation, 8 and to exert intestinal anti-inflammatory activity in the TNBS model of rat colitis, 9 making it a suitable candidate to be developed in IBD treatment.…”