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 TNFalpha and LTB(4), inhibition of the expression of IFNgamma and iNOS, and lower colonic leukocyte infiltration. The in vitro assays revealed that UR-1505 also inhibited T-lymphocyte proliferation and IL-12/IFNgamma production, two of the main pro-inflammatory cytokines involved in the pathogenesis of CD. However, UR-1505 did not modify LPS- nor IFNgamma-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.
Bailón
Elvira
E
Department of Pharmacology, CIBER-EHD, School of Pharmacy, University of Granada, Spain.
Camuesco
Desirée
D
Nieto
Ana
A
Concha
Angel
A
Fernández de Arriba
Alberto
A
Román
Juan
J
Ramis
Isabel
I
Merlos
Manuel
M
Zarzuelo
Antonio
A
Gálvez
Julio
J
Comalada
Mònica
M
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003424:Crohn Disease / Q000188:drug therapy; D004195:Disease Models, Animal; D005260:Female; D005978:Glutathione / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics; D007975:Leukotriene B4 / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012459:Salicylates / Q000627:therapeutic use*; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D014302:Trinitrobenzenesulfonic Acid; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D005466:Fluorocarbons
D000893:Anti-Inflammatory Agents; D005978:Glutathione; D007371:Interferon-gamma; D007975:Leukotriene B4; D052247:Nitric Oxide Synthase Type II; D012459:Salicylates; D014302:Trinitrobenzenesulfonic Acid; D014409:Tumor Necrosis Factor-alpha; C496318:Nos2 protein, rat; C522458:2-hydroxy-4-(2,2,3,3,3-pentafluoropropoxy)benzoic acid; D005466:Fluorocarbons