Gingerol derivatives modulate T-cell receptor mediated effects in a whole blood assay and in T-cells via 5-HT1A receptor-dependent mechanisms

Abstract

The rhizome of ginger (Zingiber officinale Roscoe) is widely used for digestive complaints, emesis, as well as inflammatory diseases, such as arthritis. Gingerol-derivatives have been reported to inhibit prostaglandin production, to indirectly modulate 5-HT3 receptor signalling, and also to influence calcium homeostasis. In order to assess the immunomodulatory potential of ginger we have profiled the effects of different ginger extracts in differentially stimulated whole blood. The model is more stable than assays with purified cells and the read-out is meaningful with regard to physiological function. Our experiments show that different ginger extracts (10–50µg/ml) and isolated pungent compounds specifically inhibit cytokine production in human whole blood after treatment with CD3 antibody, indicating a T-cell mediated process. Ethanolic and CO2 ginger extracts (10–50µg/ml) significantly inhibited CD3-stimulated Ca2+ release from intracellular stores in Jurkat T-cells, whereas a series of pure compounds showed similar, stimulatory, or no effects. To reduce these findings to a possible common denominator we postulated an effect on serotonin receptors as one possible mechanism. Serotonin can reach µM concentrations in whole blood and is known to be an important modulator of the immune response. Binding studies on the human 5-HT1A and 5-HT3 receptors led to the identification of nine compounds (8-; 10-gingerol, 6-; 8-; 10-shogaol, 1-dehydro-6-, 8-; and 10-gingerdione, as well as 6-dihydroparadol) which showed selective binding affinity to the serotonin binding site in 5HT1A receptors (Ki values=3 to 20µM). Moreover, ginger extracts inhibited the stimulatory effect of serotonin on CD3-stimulated calcium release in Jurkat cells. This is the first report on the immunomodulatory effects of gingerol-derivatives mediated, at least in part, via 5HT1A receptor interaction.