UR-1505, a new salicylate, blocks T cell activation through nuclear factor of activated T cells.
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 microM) 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 G1/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)-gamma 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-gamma mRNA expression, UR-1505 specifically inhibited NF-AT DNA binding without effect on nuclear factor-kappaB 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.
Román
Juan
J
Palau Pharma, S.A., Pharmacology and Toxicology, Polígon Industrial Riera de Caldes, Avinguda Camí Reial, 51-57, 08184 Palau-solità i Plegamans (Barcelona) Spain. jroman@palaupharma.com
de Arriba
Alberto Fernández
AF
Barrón
Sonia
S
Michelena
Pedro
P
Giral
Marta
M
Merlos
Manuel
M
Bailón
Elvira
E
Comalada
Mònica
M
Gálvez
Julio
J
Zarzuelo
Antonio
A
Ramis
Isabel
I
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016207:Cytokines / Q000096:biosynthesis; D004247:DNA / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics; D015848:Interleukin-5 / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D015759:Ionomycin / Q000494:pharmacology; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects*; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors / Q000502:physiology*; D010766:Phosphorylation; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors; D050791:STAT Transcription Factors / Q000502:physiology; D012459:Salicylates / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects*; D005466:Fluorocarbons
D050760:Cyclin-Dependent Kinase Inhibitor p27; D016207:Cytokines; D004247:DNA; D007371:Interferon-gamma; D015848:Interleukin-5; D047908:Intracellular Signaling Peptides and Proteins; D015759:Ionomycin; D050778:NFATC Transcription Factors; D011948:Receptors, Antigen, T-Cell; D050791:STAT Transcription Factors; D012459:Salicylates; C436291:CDKN1B protein, human; C522458:2-hydroxy-4-(2,2,3,3,3-pentafluoropropoxy)benzoic acid; D005466:Fluorocarbons