In vitro modulatory effects of interleukin-3 on macrophage activation induced by interleukin-2

BACKGROUND: The concomitant activation of macrophage-mediated immunosuppressive events might represent one of the most important biologic factors responsible for the decreased efficacy of cancer immunotherapies, including that of interleukin (IL)-2. In previous studies, the authors observed that the increase in the soluble IL-2 receptor (SIL-2R) and neopterin levels was related to the generation of macrophage-mediated immunosuppression and associated with a reduced clinical efficacy during IL-2 cancer immunotherapy. Because both cytokines and neurohormones may influence the macrophage system, the current study was done to evaluate the effects of IL-3 and of the pineal hormone melatonin (MLT) on monocyte response to IL-2 administration. METHODS: Peripheral blood monocytes were incubated with different concentrations of IL-2, IL-3, and MLT, either alone or in association. RESULTS: SIL-2R, neopterin, and tumor necrosis factor-alpha mean concentrations in the medium significantly increased during incubation with IL-2 at a concentration of 100 Cetus units/ml. IL-3 alone, at a dose of 10 ng/ml, also stimulated tumor necrosis factor release; no effect was found on SIL-2R and neopterin. The IL-2-induced neopterin rise was blocked by a concomitant incubation with IL-3 at a dose of 10 ng/ml. Finally, the concomitant incubation with IL-3 and MLT further inhibited neopterin release and significantly decreased IL-2-induced SIL-2R secretion. CONCLUSIONS: These results suggest that IL-3 alone or in association with MLT may modulate macrophage functions during cancer immunotherapy with IL-2 and decrease the IL-2-induced macrophage activation.