Inhibitory Effect of Farnesylthiosalicylic Acid on Mediators Release by Mast Cells: Preferential Inhibition of Prostaglandin D2 and Tumor Necrosis Factor-α Release

Abstract

There is substantial evidence suggesting that the Ras inhibitor farnesylthiosalicylic acid (FTS) may modulate various aspects of immune function and inflammation in addition to its well known anti-cancer activity. In this regard, we have recently shown that FTS suppresses T lymphocyte-mediated immune responses. Mast cells (MC), the main effector cells in the elicitation of the allergic response, are known to secrete granule-associated mediators and to release prostaglandins and cytokines on FCεRI-cross-linking, thereby contributing to the pathogenesis of allergic diseases. We hypothesized that MC act as an additional target for FTS. In the present work we analyze the effects of FTS on MC degranulation, prostaglandin release, and cytokine release in vitro, and on the elicitation of IgE-mediated MC dependent cutaneous allergic inflammation in vivo. First we have established that FTS inhibited Ras activation in MC. Next, we have shown that FTS preferentially inhibited prostaglandin (PG) D(2) and tumor necrosis factor (TNF)-α release without having any significant effect on MC β-hexosaminidase secretion. In vivo administration of FTS inhibited the late phase of passive cutaneous anaphylaxis reaction. The time course of FTS-induced inhibition in vivo correlated with mediators release and not with degranulation. This data suggests that FTS may have an inhibitory effect on MC mediated allergic inflammation, and thus may be considered as a possible therapeutic modality.

Mediators Released During Human Anaphylaxis

“…These include the Ras inhibitor farnesylthiosalicylic acid, which reduces prostaglandin D 2 and TNF-α production [76]; chrysin, which decreases histamine, TNF-α, IL-1β, IL-4, and IL-6 production [77]; allergin-1, an immunoglobulinlike receptor expressed on mast cells [78]; and U63A05, a novel synthetic compound that inhibits Syk activation in mast cells and suppresses degranulation and TNF-α and IL-4 production [79].…”

Mitochondria Distinguish Granule-Stored from de novo Synthesized Tumor Necrosis Factor Secretion in Human Mast Cells

“…Moreover, only SP concentrations higher than 1 μM were reported to be able to enhance the rate of oxygen consumption of isolated cardiac cell mitochondria 35 . Other authors had reported secretion of preformed TNF from mast cells in different species by different triggers 4, 36, 37 . However, there was no attempt to investigate how this secretion differs from de novo synthesis and release.…”

Therapeutic effect of farnesylthiosalicylic acid on adjuvant-induced arthritis through suppressed release of inflammatory cytokines

“…Ras proteins play an important role in cancer and in other biological phenomena, especially in activation of the immune system . In lymphocytes, Ras proteins regulate signalling downstream of the antigen receptor, as well as the secretion, adhesion and proliferation of cytokines .…”