Aspirin modulates interleukin-3 production: additional explanation for the preventive effects of aspirin in antiphospholipid antibody syndrome

Abstract

Objective: The granulocyte macrophage colony stimulating factors (GMCSF) and interleukin-3 (IL-3) are defined as positive signals for pregnancy, since they support the process of trophoblast invasion and expansion and induce placental growth and development. Aspirin and IL-3 were shown to be effective in preventing the manifestations of experimental antiphospholipid antibody syndrome (APS). Aspirin inhibits the activity of the enzyme cyclooxygenase in macrophages, which leads to a shift in the arachidonic acid metabolism toward the lipoxygenase pathway, and results in overproduction of leukotrienes. Our data indicated that leukotrienes are capable of stimulating IL-3 production in vitro. Our aim was to examine whether aspirin may exert its beneficial effect in APS not only by its ability to prevent thromboxane A2 production and prostaglandin I2 (PGI2) formation, but also by stimulating IL-3 production.

Methods: Splenocytes and macrophages from naive mice were cultured in vitro with low dose aspirin. Nordihydroguaiaretic acid (NDGA), an inhibitor of 5-lipoxygenase, was added to mixed cultures of splenocytes and macrophages containing low dose aspirin. IL-3 production was observed.

Results: When splenocytes and macrophages were cultured in vitro with low dose aspirin (10 micrograms/ml), a marked stimulation of IL-3 production was noted. When NDGA was added to mixed cultures of splenocytes and macrophages containing low dose aspirin, it decreased the IL-3 production. Higher dose of aspirin did not affect the cytokine production. When splenocytes were incubated without the addition of exogenous macrophages, no stimulation of IL-3 production was noted. However, when purified leukotriene B4 or leukotriene C4 was added, there was an increase of 71 and 261%, respectively, in the stimulation of IL-3 production (p < 0/01). These results were supported by in vivo studies, in which a higher serum IL-3 level was detected in mice fed low dose aspirin, compared to the control group and to mice fed a higher dose of aspirin.

Conclusion: Aspirin acts as a potent stimulator of IL-3 through its ability to raise leukotriene production, which induces production of IL-3 both in vitro and in vivo.