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

Abstract

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.

Tropisetron improved testicular inflammation in the streptozotocin‐induced diabetic rats: The role of toll‐like receptor 4 (TLR4) and mir146a

“…[ 26,33,41 ] Similarly, Karimollah et al reported that tropisetron modulates immune responses in lipopolysaccharide (LPS)‐stimulated peripheral blood mononuclear cells (PBMCs) by decreasing TLR2, TLR4, TNF‐α, and IL‐1β. [ 28 ] Herein, it appears that tropisetron ameliorated diabetes‐induced testicular inflammation by attenuating the TLR4/IRAK1/TRAF6 pathway reducing the NF‐κB activity, and finally decreasing the TNF‐α and IL‐1β levels. Furthermore, glibenclamide is a drug being used in the DM1 treatment, which acts by inhibiting the ATP‐sensitive K + channels.…”

“…[25][26][27] Tropisetron decreases TLR2, TLR4, and NF-κB in animals and humans. [28,29] Tropisetron also is an inhibitory target for calcineurin, a Ca 2+ /calmodulin-dependent phosphatase, which can mediate T-cell stimulation contributing to its anti-inflammatory properties. [23] Moreover, tropisetron plays a key role in lowering plasma glucose and improving diabetes by decrement of pancreatic oxidative stress and apoptosis.…”

Immune Cell-Related Genes in Juvenile Idiopathic Arthritis Identified Using Transcriptomic and Single-Cell Sequencing Data

“…Among the 54 potential drug targets postulated to regulate the key genes in this study, potential targets associated with the JUN gene included various drugs that have been approved for use, such as antihistamines, lipid regulators, antibiotics, antitumor agents, neurological agents, and others. Among these, diphenhydramine hydrochloride, an antihistamine has been employed to inhibit Th17-related autoimmune inflammatory diseases [ 38 ]; tropisetron, a 5-HT3 receptor antagonist, has been shown to balance the immune response through the JAK2/STAT3 signaling pathway [ 39 ]; lipid-regulating fibrates, which are well-recognized anti-inflammatory agents, such as fenofibrate, have been shown to both inhibit Th17 cells [ 40 ] and enhance the differentiation of mouse Foxp3+ Tregs cells in vitro [ 41 ]; clofibrate has been shown to reduce inflammatory signaling by suppressing NF-κB translocation [ 42 ]; clotrimazole, an antifungal agent, has been shown to enhance the T-cell response by modulating dendritic cell-mediated antigen presentation [ 43 ]; and colchicine, which is employed for the clinical treatment of gouty arthritis, has been elucidated to possess broad anti-inflammatory properties and reduce cytokine production by impeding the activation of inflammatory vesicles [ 44 ].…”

Protective Effect of Unfractionated Heparin on Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome in Neonatal Mice via the JAK2/STAT3 Signaling Pathway

“…As a potent anti-inflammatory cytokine, IL-10 plays an important role in the initiation and maintenance of immune tolerance and homeostasis [57]. IL-10 could activate STAT3 to exert its inhibitory effects on activated immune response [58]. Besides, IL-10 is also involved in the activation of JAK2 [59].…”