P045 5-Aminosalicylates promote inflammation resolution in ulcerative colitis through generation of anti-inflammatory hydroxy fatty acids
Wysoczanski R.*1, Kendall A.2, Motwani M.3, Vega R.4, Rahman F.4, McCartney S.4, Bloom S.4, Nicolaou A.2, Gilroy D.3, Segal A.1, Marks D.1,4
1University College London, Molecular Medicine, London, United Kingdom 2University of Manchester, Division of Pharmacy and Optometry, Manchester, United Kingdom 3University College London, Clinical Pharmacology, London, United Kingdom 4University College London Hospital, Gastroenterology, London, United Kingdom
5-aminosalicylate (5-ASA) drugs constitute a major therapeutic option for ulcerative colitis (UC), but their mechanism of action remains incompletely understood. We employed an
Acute inflammation was provoked by intradermal injection of killed
An excessive inflammatory reaction clinically observed in UC was normalised in patients taking 5-ASA therapy. This enhanced resolution was associated with increased concentrations of the hydroxy fatty acids 9-oxo-octadecadienoic acid (OxoODE) and 13-OxoODE. To characterise the effect of these novel mediators, cultured macrophages were co-incubated with EC, in the presence of increasing concentrations of either 9-OxoODE or 13-OxoODE. 9-OxoODE led to a dose-dependent suppression of both TNF-α (p=0.0001) and MIP-1β secretion (p=0.002), and 13-OxoODE inhibited TNF-α secretion (p=0.01), at concentrations reflective of those detected in the
9-OxoODE was more potent than 13-OxoODE for TNF-α inhibition, with an IC50 of 100nM. These effects were completely reversed by GW9662, an antagonist at the PPAR-γ receptor (p=0.006). Notably, the
We have uncovered an important novel pathway through which 5-ASAs normalise the overly exuberant acute inflammatory response in UC, by generation of hydroxy fatty acids that harness a previously unexplored pro-resolution pathway. These exert anti-inflammatory actions through the PPAR-γ receptor, providing potential new drug targets in this disease.