Tropisetron Via Alpha 7 Nicotinic Acetylcholine Receptor Suppresses Tumor Necrosis Factor-Alpha-Mediated Cell Responses Of Human Keratinocytes

Tropisetron is a serotonin receptor (5-HT-R)-modulating agent and approved as an antiemetic for patients undergoing chemotherapy. In the gut, it acts via specific serotonin receptors, 5-HT3-R, to elicit its beneficial effects against nausea. We investigated whether tropisetron can affect inflammatory cell responses of human primary epidermal keratinocytes (NHK) which are key cells in the regulation of skin homoeostasis. Tropisetron significantly and dose-dependently suppressed tumor necrosis factor (TNF)-alpha-mediated mRNA expression and protein secretion of interleukin (IL)-6 and IL-8 in these cells. This effect of tropisetron was independent of p65/NF-kappa B as shown by various NF-kappa B signal transduction read-outs. Importantly, the anti-inflammatory tropisetron effect on NHK was neither mediated by 5-HT3-R nor 5-HT4-R since these receptors were absent in NHK. In contrast, NHK expressed alpha 7 nicotinic acetylcholine receptors (alpha 7nAchR) which previously were found to bind tropisetron. The alpha 7nAchR antagonist a-bungarotoxin neutralized, whereas AR-R17779, a specific alpha 7nAchR agonist, mimicked the suppressive effect of tropisetron on TNF-alpha-mediated IL-6 and IL-8 expression in NHK. Our findings suggest that tropisetron and probably other alpha 7nAchR-activating agents could be useful for the future therapy of inflammatory skin diseases.