Tropisetron balances immune responses via TLR2, TLR4 and JAK2/STAT3 signalling pathway in LPS-stimulated PBMCs.

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-1ß, 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-1ß, 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.

Circulating levels of interleukin (IL)-12 and IL-13 in Helicobacter pylori-infected patients, and their associations with bacterial CagA and VacA virulence factors.

OBJECTIVE: The aim of this study was to determine the association of the Helicobacter pylori virulence factors, cytotoxin-associated gene A (CagA) and vacuolating cytotoxin A (VacA) antibodies, with serum levels of interleukin (IL)-12 and IL-13 in H. pylori-infected duodenal ulcer (DU) patients and H. pylori-infected asymptomatic (AS) carriers in order to elucidate any correlation between them. METHODS: A total of 67 DU patients, 48 AS individuals, and 26 healthy H. pylori-negative subjects were enrolled in this study. Serum concentrations of IL-12 and IL-13 were determined by enzyme-linked immunosorbent assay (ELISA) method. Patient sera were tested by Western blot method to determine the presence of serum antibodies to bacterial virulence antigens p120 (CagA) and p95 (VacA). Serum concentrations of IL-12 and IL-13 were compared in 9 groups, including 4 AS phenotypes (CagA⁺VacA⁺, CagA⁺VacA⁻, CagA⁻VacA⁺, CagA⁻VacA⁻), 4 DU phenotypes (CagA⁺VacA⁺, CagA⁺VacA⁻, CagA⁻VacA⁺, CagA⁻VacA⁻), and 1 control group. RESULTS: The results revealed that DU patients positive for CagA, independent of the anti-VacA antibody status, showed drastically elevated levels of IL-12 (251 ± 43 pg/ml) when compared with the other groups (p = 0.0001). No significant difference was found between groups regarding levels of IL-13 (p > 0.05). CONCLUSIONS: Our findings indicate that in the DU group, the serum concentrations of IL-12 but not of IL-13 were influenced by bacterial CagA, independent of the VacA status, suggesting that high IL-12 levels may contribute to susceptibility to DU in CagA-positive individuals. These findings could possibly be considered to improve the predictive or prognostic values of inflammatory cytokines for DU, and also to design possible novel therapeutic approaches.