Interleukin-12 inhibits eosinophil differentiation from bone marrow stem cells in an interferon-γ-dependent manner in a mouse model of asthma

Background: Intrapulmonary administration of IL-12 has been shown to inhibit the number of eosinophils in lung murine models of asthma, but the precise mechanism of this inhibition has not been reported. The purpose of this study was to examine whether IL-12 treatment inhibits bone marrow eosinophilopoiesis, and to elucidate the role of IFN-γ in this process. Objective: To elucidate the in vivo and in vitro effects of IL-12 on eosinophil differentiation from murine bone marrow (BM) stem cells, and to examine the mechanistic role of IFN-γ in this process. Methods: Allergen-sensitized BALB/c mice were administered low doses of intranasal IL-12 at the time of allergen challenge, and the number of eosinophils in BM was determined 3 days later. The direct actions of IL-12 on eosinophil differentiation from BM cells were determined in vitro. The mechanistic role of IFN-γ was assessed by measuring IFN-γ induction by IL-12 in BM cell cultures, and through the use of IFN-γ KO mice. Results: Treatment of allergic mice with intrapulmonary IL-12 (1 ng or 10 ng) reduced eosinophils in BM by 43%. Culture of BM cells from allergen-sensitized mice with IL-3 + IL-5 induced eosinophil differentiation in vitro. Addition of IL-12 to these cultures inhibited eosinophil differentiation, with maximal inhibition (45%) occurring at 10 ng/mL IL-12 concentration. IL-12 induced IFN-γ production from BM cultures, and failed to inhibit eosinophil differentiation in IFN-γ-knockout mice, indicating a critical mechanistic role for IFN-γ. Conclusion: This study demonstrates that IL-12 selectively inhibits BM eosinophilopoiesis, and that this effect is mediated by IFN-γ. Intrapulmonary IL-12 has suppressive effects on BM eosinophilopoiesis that may represent a novel mechanism contributing to the anti-eosinophilic effects of IL-12 in allergic airway disease.