Moreno Jose L, Mikhailenko Irina, Tondravi Mehrdad M, Keegan Achsah D
Department of Orthopedics, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
J Leukoc Biol. 2007 Dec;82(6):1542-53. doi: 10.1189/jlb.0107058. Epub 2007 Sep 12.
Multinucleated giant cells (MNG) are central players in the inflammatory response to foreign materials and in adverse responses to implants. IL-4 promotes the formation of MNG from bone marrow-derived precursors in vitro and participates in the development of the foreign body reaction in vivo. Therefore, we investigated the mechanism by which IL-4 promotes formation of MNG and engulfment of foreign bodies. We found that generation of MNG cells by IL-4 was dependent on cell density and expression of STAT6; macrophages derived from STAT6(-/-) mice were unable to form MNG in response to IL-4. No soluble factors including CCL2 or supernatants from IL-4-treated macrophages compensated for the lack of MNG cells in STAT6(-/-) cultures. We found that IL-4 must remain present during the full differentiation process and that STAT6(+/+) macrophage precursors retained their ability to differentiate into MNG over time. These MNG were able to internalize large particles efficiently, and the mononuclear STAT6(-/-) macrophages were unable to do so. Furthermore, we found that IL-4 induced expression of E-cadherin and dendritic cell-specific transmembrane protein in a STAT6-dependent manner. E-cadherin expression was critical for the formation of MNG cells by IL-4; an anti-E-cadherin antibody prevented the formation of large MNG. In addition, we found that STAT6(-/-) progenitors failed to fuse with STAT6(+/+), revealing the need for a homotypic interaction. Thus, IL-4 promotes the formation of MNG in a STAT6-dependent manner by regulating cell surface expression of E-cadherin, leading to homotypic cell fusion and the incorporation of large foreign bodies.
多核巨细胞（MNG）是对外源物质炎症反应及植入物不良反应中的核心参与者。白细胞介素-4（IL-4）在体外促进骨髓来源前体细胞形成MNG，并参与体内异物反应的发展。因此，我们研究了IL-4促进MNG形成和吞噬异物的机制。我们发现IL-4诱导MNG细胞生成依赖于细胞密度和信号转导及转录激活因子6（STAT6）的表达；源自STAT6基因敲除小鼠的巨噬细胞对IL-4无反应，无法形成MNG。包括趋化因子配体2（CCL2）或IL-4处理的巨噬细胞培养上清液在内的可溶性因子，均无法弥补STAT6基因敲除培养体系中MNG细胞的缺失。我们发现IL-4在整个分化过程中必须持续存在，且随着时间推移，STAT6基因野生型巨噬细胞前体仍保留分化为MNG的能力。这些MNG能够高效内化大颗粒物质，而单核的STAT6基因敲除巨噬细胞则无法做到。此外，我们发现IL-4以STAT6依赖的方式诱导上皮钙黏蛋白（E-cadherin）和树突状细胞特异性跨膜蛋白的表达。E-cadherin表达对IL-4诱导MNG细胞形成至关重要；抗E-cadherin抗体可阻止大型MNG的形成。另外，我们发现STAT6基因敲除祖细胞无法与STAT6基因野生型祖细胞融合，这表明需要同型相互作用。因此，IL-4通过调节E-cadherin的细胞表面表达，以STAT6依赖的方式促进MNG的形成，导致同型细胞融合并摄取大型异物。
