BACKGROUND AND PURPOSE Dersalazine sodium (DS) is a new chemical entity formed by combining, through an azo bond, a potent platelet activating factor (PAF) antagonist (UR‐12715) with 5‐aminosalicylic acid (5‐ASA). DS has been demonstrated to have anti‐inflammatory effects on trinitrobenzene sulphonic acid (TNBS)‐induced colitis in rats and recently in UC patients in phase II PoC. There is Increasing evidence that Th17 cells have an important role in the pathogenesis of inflammatory bowel disease (IBD). The aim of this study was to further characterize the anti‐inflammatory effects of DS. EXPERIMENTAL APPROACH Effect of DS (10 or 30 mg·kg−1 b.i.d.) on TNBS‐induced colitis in rats was studied after 2 and 7 days with special focus on inflammatory mediators. Additionally, its anti‐inflammatory properties were analysed in two different models of dextran sodium sulphate (DSS)‐induced colitis, BALB/c and C57BL/6 mice, the latter being dependent on IL‐17. KEY RESULTS DS, when administered for 7 days, showed intestinal anti‐inflammatory effects in TNBS‐induced colitis; these effects were observed both macroscopically and through the profile of inflammatory mediators (TNF, IL‐1β, IL‐6 and IL‐17). Although the 2 day treatment with DS did not induce intestinal anti‐inflammatory effects, it was sufficient to reduce the enhanced IL‐17 expression. DS showed beneficial effects on DSS‐induced colitis in C57BL/6 mice and reduced colonic pro‐inflammatory cytokines IL‐1β, IL‐6 and IL‐17. In contrast, it did not exert intestinal anti‐inflammatory effects on DSS‐induced colitis in BALB/c mice. CONCLUSIONS AND IMPLICATIONS DS exerts intestinal anti‐inflammatory activity in different rodent models of colitis through down‐regulation of IL‐17 expression.

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Change in the expression of a select set of genes can serve as an early biomarker, one with high specificity and sensitivity to clinical, endoscopic, and histologic responses. This could represent a new tool for identifying early response to treatment in mild to moderately active UC patients.

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.