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.


CONCLUSIONS
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.
Abteilung Kardiologie 2, Universitäts-Herzzentrum Freiburg Bad Krozingen, Südring 15, D-79189 Bad Krozingen, Germany.
Christian
C
Stratz
Harsharan S
HS
Bhatia
Ravi Shankar
RS
Akundi
Thomas
T
Nührenberg
Dietmar
D
Trenk
Eduardo
E
Muñoz
Bernd L
BL
Fiebich
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007114:Immunization; D007211:Indoles / Q000494:pharmacology*; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology; D010766:Phosphorylation / Q000187:drug effects; D012323:RNA Processing, Post-Transcriptional; D058831:Serotonin 5-HT3 Receptor Antagonists / Q000494:pharmacology*; D000077526:Tropisetron; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D007211:Indoles; D007375:Interleukin-1; D008070:Lipopolysaccharides; D058831:Serotonin 5-HT3 Receptor Antagonists; D014409:Tumor Necrosis Factor-alpha; D000077526:Tropisetron; D048051:p38 Mitogen-Activated Protein Kinases