Anti-Inflammatory Effects of Analogues of N-Acyl Homoserine Lactones on Eukaryotic Cells.
BACKGROUND
Since acyl-homoserine lactone (AHL) profiling has been described in the gut of healthy subjects and patients with inflammatory bowel disease (IBD), the potential effects of these molecules on host cells have raised interest in the medical community. In particular, natural AHLs such as the 3-oxo-C12-HSL exhibit anti-inflammatory properties. Our study aimed at finding stable 3-oxo-C12-HSL-derived analogues with improved anti-inflammatory effects on epithelial and immune cells.


METHODS
We first studied the stability and biological properties of the natural 3-oxo-C12-HSL on eukaryotic cells and a bacterial reporter strain. We then constructed and screened a library of 22 AHL-derived molecules. Anti-inflammatory effects were assessed by cytokine release in an epithelial cell model, Caco-2, and a murine macrophage cell line, RAW264.7, (respectively, IL-8 and IL-6) upon exposure to the molecule and after appropriate stimulation (respectively, TNF-α 50 ng/mL and IFN-γ 50 ng/mL, and LPS 10 ng/mL and IFN-γ 20 U/mL).


RESULTS
We found two molecules of interest with amplified anti-inflammatory effects on mammalian cells without bacterial-activating properties in the reporter strain. The molecules furthermore showed improved stability in biological medium compared to the native 3-oxo-C12-HSL.


CONCLUSIONS
We provide new bio-inspired AHL analogues with strong anti-inflammatory properties that will need further study from a therapeutic perspective.
['Peyrottes|Agathe|A|', 'Coquant|Garance|G|', 'Brot|Loïc|L|0000-0002-6977-4253', 'Rainteau|Dominique|D|', 'Seksik|Philippe|P|0000-0003-3596-9893', 'Grill|Jean-Pierre|JP|', 'Mallet|Jean-Maurice|JM|0000-0001-8570-9542']
D054742:Acyl-Butyrolactones D000704:Analysis of Variance D000818:Animals D000893:Anti-Inflammatory Agents D000069196:Gastrointestinal Microbiome D015212:Inflammatory Bowel Diseases D051379:Mice D011760:Pyrrolidinones D000067996:RAW 264.7 Cells
AHL inflammatory bowel disease gut microbiota