Involvement of IGF-1 and Akt in M1/M2 activation state in bone marrow-derived macrophages
Involvement of IGF-1 and Akt in M1/M2 activation state in bone marrow-derived macrophages
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DOI：
10.1016/j.yexcr.2015.05.015
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发表时间：
2015-07-15
影响因子：
3.7
通讯作者：
Lynch, Marina A.
中科院分区：
文献类型：
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作者：
Barrett, James P.;Minogue, Aedin M.;Lynch, Marina A.
巨噬细胞可以被极化以采用M1或M2表型，激活的功能结果包括免疫分子如胰岛素样生长因子（IGF）-1的分泌改变以及与每种状态特异性相关的细胞表面分子的上调。白细胞介素（IL）-4通过两种受体（I型和II型受体）介导其作用，并且这些受体的活化导致信号转导子和转录激活子（STAT）6的磷酸化。JAK 3由于I型IL-4 R的连接而被激活，所述I型IL-4 R参与Akt激活。我们着手研究干扰IGF-1音调对IL-4和干扰素（IFN）γ诱导的激活的影响，这可能发生的机制和I型IL-4 R激活对M2状态的贡献。本文提供的数据表明，IL-4诱导的Akt活化是JAK 3依赖性的，通过IGF-1的释放而增强，并且是完全采用M2表型所必需的，因为阻断IGF-1活性减弱了IL-4诱导Akt活化和上调一些M2相关分子表达的能力。此外，观察到甘露糖受体（MRC 1）、几丁质酶-1（Arg-1）、几丁质酶-3样3（Chi 313）和在炎症区1中发现的（FIZZ 1）的表达的差异控制。IFN γ诱导的IGF-1减少因磷脂酰肌醇-3（PI 3）激酶的抑制而加剧，表明Akt可能通过IGF-1调节其自身的激活。总体而言，IGF-1/Akt信号传导的缺陷与诱导M2状态的能力降低和对IFN γ的反应性增加相关。(C)2015 Elsevier Inc. All rights reserved.
Macrophages can be polarised to adopt the M1 or M2 phenotype and functional outcomes of activation include altered secretion of immune molecules such as insulin-like growth factor (IGF)-1 as well as upregulation of cell surface molecules specifically associated with each state. Interleukin (IL)-4 mediates its effects through two receptors, the type I and II receptors and activation of these receptors results in phosphorylation of signal transducers and activators of transcription (STAT)6. JAK3 is activated as a consequence of ligation of the type I IL-4R, which participates in Akt activation. We set out to investigate the impact of perturbation of IGF-1 tone on IL-4- and interferon (IFN)gamma-induced activation, the mechanisms by which this may occur and the contribution of type I IL-4R activation to adoption of the M2 state. The data presented here indicate that IL-4-induced activation of Akt is JAK3-dependent, enhanced by release of IGF-1 and necessary for full adoption of the M2 phenotype, since blocking IGF-1 activity blunts the ability of IL-4 to induce activation of Akt and to upregulate expression of some M2-associated molecules. In addition, differential control of the expression of mannose receptor (MRC1), arginase-1 (Arg-1), chitinase-3 like 3 (Chi313) and found in inflammatory zone 1 (FIZZ1) was observed. The IFN gamma-induced decrease in IGF-1 was exacerbated by inhibition of phosphatidylinositol-3 (PI3) kinase, indicating that Akt may regulate its own activation via IGF-1. Overall, a deficit in IGF-1/Akt signalling is associated with decreased capacity to induce the M2 state and an increased responsiveness to IFN gamma. (C) 2015 Elsevier Inc. All rights reserved.