Arising from: Riley G (2008) Tendinopathy—from basic science to treatment Nat Clin Pract Rheumatol (2008) 4: 82–89 (doi:10.1038/ncprheum0700)

Dear Editor,

In a Review published in the February 2008 issue of Nature Clinical Practice Rheumatology, Riley discussed the molecular pathology of tendinopathy and novel and specific molecular targets for therapy.1 In evaluating the potential therapies for tendinopathy, however, the role of the 5-hydroxytryptamine (5-HT) 3 receptor antagonists with anti-inflammatory properties, such as tropisetron, was not discussed.

5-HT (serotonin) is a well-characterized neurotransmitter widely distributed in the central nervous system. Furthermore, 5-HT is released in peripheral tissues by platelets, mast cells and noradrenergic nerve terminals that are in close contact with immune cells in lymphoid organs. 5-HT is found in the immune–inflammatory axis and has been shown to influence the immune response in mammals.2 The 5-HT3 receptor subtype has been found to be expressed in cells of the immune system including human T-cells.3 5-HT can modulate the T-cell function through activation of 5-HT3 receptors. In vitro studies have shown that blockade of 5-HT3 receptors reduces the release of tumor necrosis factor (TNF), interleukin (IL)-1β, and IL-2. There is evidence from both human and animal studies that 5-HT3 receptor antagonists, particularly tropisetron, possess analgesic and anti-inflammatory effects. Fiebich et al. have shown that in human monocytes both lipopolysaccharide-stimulated TNF and IL-1β secretion were inhibited by tropisetron in a dose-dependent manner.4

The findings of a recent study provide new mechanistic insights into the anti-inflammatory/immunosuppressive activities of tropisetron, which might be independent of 5-HT3 receptor signaling. De la Vega et al. demonstrated that tropisetron inhibits antigen-induced proliferation and IL-2 production in human peripheral T-cells. They also identified calcineurin as one of the main targets for the inhibitory effect of tropisetron in T-cell activation.5 Calcineurin is a calcium-activated serine–threonine phosphatase that is critical to a number of developmental processes in the cardiovascular, nervous and immune systems. In the T-cell lineage, calcineurin activation is important for pre-T-cell receptor signaling, T-cell receptor-mediated positive selection of thymocytes into mature T-cells, and many aspects of the immune response. The critical role of calcineurin in the immune response is underscored by the fact that calcineurin inhibitors, such as ciclosporin and tacrolimus, are powerful immunosuppressants in wide clinical use.

Preliminary data have shown tropisetron to have clinical benefit in patients with chronic inflammatory joint disease and soft tissue rheumatism.6 Therefore, we suggest 5-HT3 receptors contribute to the inflammatory processes involved in tendinopathies and that the use of 5-HT3 receptor agonists is of therapeutic benefit. Tropisetron is widely used as an efficacious agent in counteracting chemotherapy-induced emesis. A drug discovered to possess one property, when subjected to scrutiny, is often found to have another. Tropisteron is well tolerated and, as a lead compound, might serve for development of new compounds with fewer adverse effects than classic anti-inflammatory drugs.