Urocanic acid (UCA) derivatives were tested for their anti-inflammatory activity in inflammatory bowel disease (IBD) in two models: ex vivo and an experimental mouse model. Ex vivo: inflamed colonic tissue was incubated in culture medium with or without the UCA derivatives. Biopsies, incubated with UCA derivatives, produced lower levels of proinflammatory cytokines IL-6 and IL-8 as compared to control biopsies. The same compounds also showed increased levels of IL-10, providing an additional indication for anti-inflammatory properties. In vivo: a combination of two imidazoles and a combination of two of their ethyl esters were administered to mice while colitis was induced by oral administration of dextran sodium sulfate (DSS). Some parameters did not show conclusive effects, but the imidazoles and their ethyl esters reduced the area of inflammation and the number of infiltrating neutrophils. Fibrosis and the sum of all histological aspects were reduced by the imidazoles, whereas the ethyl esters reduced the colon weight to length ratio. These results suggest that the UCA derivatives have anti-inflammatory effect on IBD. In addition, fine tuning of the ex vivo model may provide an elegant way to predict anti-inflammatory effects of potential drugs in humans, which may decrease the need for animal experiments. 1. Introduction Inflammatory bowel diseases are chronic inflammatory diseases of the gastrointestinal tract resulting from a complex interaction of genetic, immunologic, and environmental factors. Two major forms of IBD are described: Crohn’s disease and ulcerative colitis. Increased numbers of activated immune cells are present in the intestinal mucosa of IBD patients, resulting in enhanced cytokine levels of tumor necrosis factor-α and interleukins (IL), such as IL-6, IL-17, IL-10 [1], and IL-8 [2]. These cytokines are important mediators for interaction between immune, epithelial, and mesenchymal cells [3]. Biologic agents, antagonizing TNF-α, are effective in IBD patients to induce and maintain disease remission. However, not all patients benefit from this strategy [4, 5]. Other current approaches, such as biologic agents antagonizing proinflammatory cytokines (e.g., IL-6) or the ones that favour increased levels of the suppressive cytokine IL-10, did not result in a substantial reduction of IBD disease activity in clinical trials [6]. Therefore, new therapeutic strategies are urgently required that may be based on small-molecular compounds, rather than biologic agents. Here we present a new class of small-molecular compounds, the UCA
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