The anti-inflammatory effects of the 5-HT₃ receptor antagonist tropisetron are mediated by the inhibition of p38 MAPK activation in primary human monocytes.

Background: There is evidence from human and animal research that 5-hydroxytryptamine (5-HT) 3 receptor antagonists, particularly tropisetron, exert analgesic and anti-inflammatory activity. We have demonstrated that tropisetron inhibited lipopolysaccharide (LPS)-stimulated tumor necrosis factor (TNF)alpha and interleukin-(IL-)1beta release in primary human monocytes. The underlying mechanisms of these effects have not been investigated in detail so far.

Methods: The molecular mechanisms of the anti-inflammatory effects of tropisetron were investigated in human primary monocytes in vitro by studying IL-1beta and TNFalpha mRNA levels by PCR and reporter gene assay and by elucidating the phosphorylation of p38 mitogen activated kinase (MAPK) by Western blot.

Results: The steady state levels of IL-1beta and TNFalpha mRNA in LPS-activated human peripheral monocytes and the transcriptional activity of the TNFalpha promoter were not inhibited by tropisetron, suggesting that the inhibitory activity of this 5-HT₃ receptor antagonist takes place at the post-transcriptional level. Additionally, we found that tropisetron prevents the phosphorylation and thus activation of the p38 MAPK, which is involved in post-transcriptional regulation of various cytokines.

Conclusion: Our data indicate that the anti-inflammatory effects of the 5-HT₃ receptor antagonist tropisetron, as shown in vivo, are possibly mediated by a selective inhibition of pro-inflammatory cytokines at the post-transcriptional level. 5-HT₃ receptor antagonists are therefore a new and promising therapeutic option. New and more selective--in respect to the 5-HT₃ subtypes--5-HT₃R antagonists might be a future perspective in the pharmacological treatment of inflammatory diseases.