Phenolic Acid-Amino Acid Adducts Exert Distinct Immunomodulatory Effects in Macrophages Compared to Parent Phenolic Acids.

Caffeic acid (CA) and chlorogenic acid (CGA) are commonly found phenolic acids in plant-derived foods and beverages. Their corresponding adducts with cysteine (Cys) have been detected in coffee-containing beverages. However, despite the well-documented antioxidant and anti-inflammatory activity of CA and CGA, the immunomodulatory activities of the Cys adducts (CA-Cys and CGA-Cys) are unknown. The adducts were therefore synthesized, and their immunomodulatory effects were studied in lipopolysaccharide (LPS)-treated RAW 264.7 cells and compared to the activity of the parent phenolic acids. CA and CGA generally down-regulated the inflammatory responses. However, RNA-sequencing showed that the LPS-induced pathways related to Toll-like receptor signaling, chemokine signaling, and NOD-like receptor signaling, and JAK-STAT/MAPK signaling pathways were upregulated in adduct-treated cells relative to parent phenolic acids, while neurodegenerative disorder-related pathways and metabolic pathways were downregulated. Production of prostaglandin E (PGE), interleukin-6, tumor necrosis factor-α (TNF-α), and reactive oxygen species (ROS) was all inhibited by CA and CGA ( < 0.05). PGE and TNF-α were further suppressed in adduct-stimulated cells ( < 0.05), but ROS production was increased. For example, TNF-α produced by 100 μM CGA-stimulated cells and 100 μM CGA-Cys adduct-stimulated cells were 4.46 ± 0.23 and 1.61 ± 0.18 ng/mL, respectively. Thus, the addition of the Cys moiety drastically alters the anti-inflammatory activity of phenolic compounds.