SHIP Represses the Generation of IL-3-Induced M2 Macrophages by Inhibiting IL-4 Production from Basophils
SHIP Represses the Generation of IL-3-Induced M2 Macrophages by Inhibiting IL-4 Production from Basophils
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DOI：
10.4049/jimmunol.0900864
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发表时间：
2009-09-15
影响因子：
4.4
通讯作者：
Krystal, Gerald
中科院分区：
文献类型：
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作者：
Kuroda, Etsushi;Ho, Victor;Krystal, Gerald
由于这两种M phi亚群对肿瘤进展具有相反的作用，因此确定是什么调节经典活化（M1）与替代活化（M2）巨噬细胞（M phi s）的产生引起了极大的兴趣。我们在此表明，IL-3和GM-CSF在较小程度上使鼠M phi祖细胞偏向M2表型，特别是在不存在SHIP的情况下。具体而言，将这些细胞因子与或不与M-CSF一起添加到粘附或谱系耗尽的（Lin（-））SHIP-/-骨髓（BM）细胞中，在所得成熟M phi中诱导高水平的M2标志物、β-淀粉酶1和Ym 1。这些体外衍生的成熟Mphi还显示出其他M2特征，包括不能增强抗CD 3刺激的脾T细胞分泌IFN-γ和低IL-12以及响应于LPS的高IL-10产生。毫不奇怪，鉴于IL-3和GM-CSF利用STAT 5触发许多下游信号传导途径，当使用STAT 5（-/-）BM细胞时，这种M2表型被抑制。然而，出乎意料的是，当使用STAT 6（-/-）BM细胞时，这种M2表型也被抑制，这表明可能涉及IL-4或IL-13诱导的信号传导。与此一致，我们发现IL-3和GM-CSF刺激IL-4的产生，特别是从SHIP-/- Lin（-）BM细胞，并且中和抗IL-4 Ab阻断IL-3诱导的M2偏斜。此外，我们发现Lin（-）BM中的嗜碱性祖细胞负责IL-3和GM-CSF诱导的IL-4产生，SHIP抑制M2偏斜不是通过阻止M phi自身的偏斜，而是通过抑制嗜碱性粒细胞产生IL-4。免疫学杂志，2009，183：3652-3660.
There is a great deal of interest in determining what regulates the generation of classically activated (M1) vs alternatively activated (M2) macrophages (M phi s) because of the opposing effects that these two M phi subsets have on tumor progression. We show herein that IL-3 and, to a lesser extent, GM-CSF skew murine M phi progenitors toward an M2 phenotype, especially in the absence of SHIP. Specifically, the addition of these cytokines, with or without M-CSF, to adherence- or lineage-depleted (Lin(-)) SHIP-/- bone marrow (BM) cells induces high levels of the M2 markers, arginase 1, and Ym1 in the resulting mature M phi s. These in vitro-derived mature M phi s also display other M2 characteristics, including an inability to enhance anti-CD3-stimulated splenic T cell secretion of IFN-gamma and low IL-12 and high IL-10 production in response to LPS. Not surprisingly, given that IL-3 and GM-CSF utilize STAT5 to trigger many downstream signaling pathways, this M2 phenotype is suppressed when STAT5(-/-) BM cells are used. Unexpectedly, however, this M2 phenotype is also suppressed when STAT6(-/-) BM cells are used, suggesting that IL-4- or IL-13-induced signaling might be involved. Consistent with this, we found that IL-3 and GM-CSF stimulate the production of IL-4, especially from SHIP-/- Lin(-) BM cells, and that neutralizing anti-IL-4 Abs block IL-3-induced M2 skewing. Moreover, we found that basophil progenitors within the Lin(-) BM are responsible for this IL-3- and GM-CSF-induced IL-4 production, and that SHIP represses M2 skewing not by preventing skewing within M phi s themselves but by inhibiting IL-4 production from basophils. The Journal of Immunology, 2009, 183: 3652-3660.