Anti-Inflammatory Effects of Analogues of N-Acyl Homoserine Lactones on Eukaryotic Cells

• Published in: International journal of molecular sciences Vol. 21; no. 24; p. 9448
• Main Authors: Peyrottes, Agathe, Coquant, Garance, Brot, Loïc, Rainteau, Dominique, Seksik, Philippe, Grill, Jean-Pierre, Mallet, Jean-Maurice
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 11.12.2020; MDPI
• Subjects: Acyl-Butyrolactones - chemistry; Acyl-Butyrolactones - therapeutic use; Analysis of Variance; Animals; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - therapeutic use; Bacteria; Biological activity; By products; Gastrointestinal Microbiome - drug effects; Gene expression; Inflammatory Bowel Diseases - drug therapy; Inflammatory Bowel Diseases - microbiology; Life Sciences; Mammals; Metabolites; Mice; Microbiota; Physiology; Pyrrolidinones - chemistry; RAW 264.7 Cells; AHL; gut microbiota; inflammatory bowel disease
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21249448

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.