Type II-Activated Murine Macrophages Produce IL-4

BackgroundType II activation of macrophages is known to support Th2 responses development; however, the role of Th2 cytokines (esp. IL-4) on type II activation is unknown. To assess whether the central Th2 cytokine IL-4 can alter type II activation of macrophages, we compared the ability of bone marrow-derived macrophages from wild type (WT) and IL-4Rα-deficient mice to be classically or type II-activated in vitro. ResultsWe found that although both WT and IL-4Rα-deficient macrophages could be classically activated by LPS or type II activated by immune complexes plus LPS, IL-4Rα-deficient macrophages consistently produced much higher levels of IL-12p40 and IL-10 than WT macrophages. Additionally, we discovered that type II macrophages from both strains were capable of producing IL-4; however, this IL-4 was not responsible for the reduced IL-12p40 and IL-10 levels produced by WT mice. Instead, we found that derivation culture conditions (GM-CSF plus IL-3 versus M-CSF) could explain the different responses of BALB/c and IL-4Rα−/− macrophages, and these cytokines shaped the ensuing macrophage such that GM-CSF plus IL-3 promoted more IL-12 and IL-4 while M-CSF led to higher IL-10 production. Finally, we found that enhanced IL-4 production is characteristic of the type II activation state as other type II-activating products showed similar results. ConclusionsTaken together, these results implicate type II activated macrophages as an important innate immune source of IL-4 that may play an important role in shaping adaptive immune responses.背景：已知巨噬细胞II型激活可辅助辅助性T细胞2型（T helper 2, Th2）免疫应答的发生发展；然而，辅助性T细胞2型细胞因子（尤其是白细胞介素4，IL-4）在巨噬细胞II型激活中的作用尚不明确。为探究核心辅助性T细胞2型细胞因子白细胞介素4（IL-4）是否可调控巨噬细胞II型激活，我们比较了野生型（wild type, WT）与白细胞介素4受体α缺陷型（IL-4Rα-deficient）小鼠的骨髓源性巨噬细胞在体外发生经典激活或II型激活的能力。结果：我们发现，尽管野生型与IL-4Rα缺陷型巨噬细胞均可经脂多糖（lipopolysaccharide, LPS）发生经典激活，或经免疫复合物联合LPS发生II型激活，但IL-4Rα缺陷型巨噬细胞持续分泌的白细胞介素12p40（IL-12p40）与白细胞介素10（IL-10）水平显著高于野生型巨噬细胞。此外，我们观察到两种品系来源的II型巨噬细胞均能分泌IL-4；但该IL-4并非导致野生型小鼠巨噬细胞IL-12p40与IL-10分泌水平降低的原因。进一步研究发现，巨噬细胞的体外诱导培养条件（粒细胞-巨噬细胞集落刺激因子（granulocyte-macrophage colony-stimulating factor, GM-CSF）联合白细胞介素3（interleukin-3, IL-3）与巨噬细胞集落刺激因子（macrophage colony-stimulating factor, M-CSF））可解释BALB/c小鼠与IL-4Rα缺陷型巨噬细胞的应答差异，且上述细胞因子可塑造巨噬细胞的功能表型：GM-CSF联合IL-3可促进更多IL-12与IL-4的分泌，而M-CSF则可诱导更高水平的IL-10产生。最后，我们发现IL-4分泌增强是巨噬细胞II型激活状态的特征之一，其他II型激活诱导物也得到了相似的实验结果。结论：综上，本研究结果表明，II型激活的巨噬细胞是IL-4的重要固有免疫来源，其可能在调控适应性免疫应答的过程中发挥关键作用。