Interleukin-4-induced β-catenin regulates the conversion of macrophages to multinucleated giant cells
Interleukin-4-induced β-catenin regulates the conversion of macrophages to multinucleated giant cells
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DOI：
10.1016/j.molimm.2012.12.004
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发表时间：
2013-06-01
影响因子：
3.6
通讯作者：
Park, Jin Mo
中科院分区：
文献类型：
--
作者：
Binder, Flora;Hayakawa, Morisada;Park, Jin Mo
细胞因子白细胞介素-4（IL-4）对巨噬细胞发挥多效性作用，因为它在对感染因子、过敏原和疫苗的免疫应答中起关键作用。暴露于IL-4的巨噬细胞急剧改变其基因表达和代谢状态，以适应新的功能需求。IL-4还诱导巨噬细胞融合在一起并形成多核巨细胞（MGCs）。MGC的形成与组织中病原微生物或异物的持续存在导致的慢性炎症有关。然而，关于IL-4诱导的巨噬细胞向MGC转化的调节机制知之甚少。我们观察到暴露于IL-4后小鼠巨噬细胞中β-连环蛋白蛋白而非mRNA量的显著增加。为了研究β-连环蛋白在巨噬细胞中的作用，我们产生了骨髓细胞特异性缺失β-连环蛋白基因的小鼠。β-连环蛋白表达的消融不影响巨噬细胞的活力或损害已知IL-4诱导基因的表达。有趣的是，与IL-4一起孵育的β-连环蛋白缺陷型巨噬细胞形成MGCs的效率明显高于野生型巨噬细胞。在注射几丁质的骨髓细胞特异性β-连环蛋白敲除小鼠的腹腔中检测到多核细胞形成的类似增加，已知几丁质诱导内源性IL-4产生。我们的研究结果揭示了β-连环蛋白作为一种新的调节巨噬细胞对IL-4的反应，并表明其表达或功能的治疗性调节可能有助于提高IL-4驱动的免疫反应的有效性或改善其病理学。(C)2012爱思唯尔有限公司保留所有权利。
The cytokine interleukin-4 (IL-4) exerts pleiotropic effects on macrophages as it plays a key role in the immune response to infectious agents, allergens, and vaccines. Macrophages exposed to IL-4 drastically change their gene expression and metabolic state to adjust to new functional requirements. IL-4 also induces macrophages to fuse together and form multinucleated giant cells (MGCs). MGC formation is associated with chronic inflammation resulting from persistence of pathogenic microorganisms or foreign materials in tissues. Very little is known, however, about the mechanisms regulating IL-4-induced macrophage-to-MGC conversion. We observed a dramatic increase in beta-catenin protein but not mRNA amount in mouse macrophages following exposure to IL-4. To investigate the role of beta-catenin in macrophages, we generated mice with a myeloid cell-specific deletion of the beta-catenin gene. Ablation of beta-catenin expression did not affect the viability of macrophages or impair expression of known IL-4-inducible genes. Intriguingly, beta-catenin-deficient macrophages incubated with IL-4 formed MGCs with markedly greater efficiency than wild-type macrophages. Similar increases in multinucleated cell formation were detected in the peritoneal cavity of myeloid cell-specific beta-catenin knockout mice injected with chitin, which is known to induce endogenous IL-4 production. Our findings reveal beta-catenin as a novel regulator of macrophage responses to IL-4, and suggest that therapeutic modulation of its expression or function may help enhance the effectiveness or ameliorate the pathology of IL-4-driven immune responses. (C) 2012 Elsevier Ltd. All rights reserved.