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Tropisetron balances immune responses via TLR2, TLR4 and JAK2/STAT3 signalling pathway in LPS‐stimulated PBMCs
Author(s) -
Karimollah Alireza,
Hemmatpur Anahid,
Hosseini Nafise,
Manshadi Mahdi Dehghan
Publication year - 2021
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/bcpt.13565
Subject(s) - tropisetron , tlr4 , tlr2 , pharmacology , immune system , toll like receptor , proinflammatory cytokine , stat3 , medicine , immunology , biology , inflammation , signal transduction , receptor , innate immune system , antagonist , microbiology and biotechnology
Numerous documents have been stated that tropisetron, an antagonist of the 5‐HT3 receptor and α7nAChR agonist, modulates immune responses. However, the mechanistic basis for this aspect of tropisetron action is largely unknown. Here, the immuno‐modulatory effects of tropisetron are investigated, focusing on the possible molecular targets and the mechanisms. Aside from the well‐characterized role in immune signalling, JAK2/STAT3, TLR2 and TLR4 are signal transducers linked to both immuno‐modulatory actions of acetylcholine and serotonin. Therefore, we evaluated their involvement in the immunoregulatory effects of tropisetron. To test the hypothesis, we assessed the expression of pro‐/anti‐inflammatory cytokines including TNF‐α, IL‐1β, IL‐17 and IL‐10 following tropisetron treatment in lipopolysaccharide (LPS)‐stimulated peripheral blood mononuclear cells (PBMCs) derived from healthy subjects. Tropisetron up‐regulates the transcription of TLR2, TLR4, JAK2 and STAT3 genes. Tropisetron also increases the expression of target pro‐inflammatory cytokines, although considerably suppresses the pro‐inflammatory cytokines (IL‐1β, IL‐17 and TNF‐α) levels in media. Tropisetron notably promotes both IL‐10 gene expression and secretion. These findings confirm the antiphlogistic properties of tropisetron. The present data also shed light on a new aspect of tropisetron immune‐modulatory action that engaged TLR2, TLR4 and JAK2/STAT3 signalling cascades.