The intestinal anti-inflammatory effects of the novel agent UR-1505 in the TNBS model of rat colitis are mediated by T-lymphocyte inhibition

UR-1505 is a novel pentafluoropropoxy derivative of salicylic acid, selected from a series of salicylate derivatives, according to their activity as inhibitors of T-lymphocyte activation. This study describes the anti-inflammatory activity of UR-1505 on trinitrobenzenesulphonic acid-induced colitis in rat, an experimental model that resembles to Crohn's disease (CD), as well as its in vitro effects on T-cells and bone marrow-derived macrophages (BMDM) activation. UR-1505 showed intestinal anti -inflammatory effect, associated with reduced colonic levels of TNF alpha and LTB4, inhibition of the expression of IFN-gamma and iNOS, and lower colonic leukocyte infiltration. The in vitro assays revealed that UR-1505 also inhibited T-lymphocyte proliferation and IL-12/IFN-gamma production, two of the main pro-inflammatory cytokines involved in the pathogenesis of CD. However, UR-1505 did not modify LPS- nor IFN-gamma-induced activation in BMDM. Thus, UR-1505 specifically affects T-cells without modifying the activation of BMDM. In conclusion, the intestinal anti-inflammatory activity of UR-1505 seems to be mediated by a reduction in the recruitment of immune cells to the inflammatory foci, together with the inhibition of T-cell activation. These results suggest that UR-1505 may be an interesting candidate to be explored for the treatment of CD. (c) 2007 Elsevier Inc. All rights reserved.