Enhanced apoptotic cell clearance capacity and B cell survival factor production by IL-10-activated macrophages: Implications for Burkitt's lymphoma
Enhanced apoptotic cell clearance capacity and B cell survival factor production by IL-10-activated macrophages: Implications for Burkitt's lymphoma
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DOI：
10.4049/jimmunol.174.5.3015
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发表时间：
2005-03-01
影响因子：
4.4
通讯作者：
Gregory, CD
中科院分区：
文献类型：
--
作者：
Ogden, CA;Pound, JD;Gregory, CD
伯基特淋巴瘤（Burkitt’s lymphoma， BL）以肿瘤细胞频繁凋亡和巨噬细胞浸润为主。由于BL细胞具有高速率凋亡的固有倾向，我们推断，BL中的巨噬细胞在功能上至少增强了两种与肿瘤发病有关的活性：1)吞噬凋亡细胞，这是一种已知的抑制免疫反应的抗炎过程；2)产生限制肿瘤细胞凋亡程度的BL细胞存活因子。在本研究中，我们发现BL微环境中富含多效性细胞因子IL-10，该因子可由肿瘤细胞和巨噬细胞产生，并且IL-10激活的人巨噬细胞体外吞噬凋亡细胞的能力增强。发现这依赖于凋亡细胞的巨噬细胞栓系受体CD14。此外，IL-10激活的巨噬细胞产生的B细胞存活因子，TNF家族的B细胞活化因子/B淋巴细胞刺激因子（BAFF/BLyS）水平明显高于无IL-10成熟的巨噬细胞。巨噬细胞与BL细胞共培养进一步增强BAFF分泌。值得注意的是，我们发现il -10激活的巨噬细胞对BL细胞存活的增强是由BAFF依赖成分介导的，BAFF是由肿瘤相关巨噬细胞原位高水平产生的。这些结果表明，受IL-10调节的巨噬细胞有可能促进BL的发病，首先，通过增强吞噬凋亡肿瘤细胞后抑制抗肿瘤免疫，其次，通过增加肿瘤细胞生长/生存因子的产生。
Burkitt's lymphoma (BL) is typified by frequent tumor cell apoptosis and significant macrophage infiltration. Since BL cells have an inherent tendency to undergo apoptosis at a high rate, we reasoned that macrophages in BL are functionally enhanced in at least two activities that have implications for tumor pathogenesis: 1) engulfment of apoptotic cells, an anti-inflammatory process known to suppress immune responses, and 2) production of BL cell survival factors that limit the extent of tumor cell apoptosis. In this study, we show that the microenvironment of BL is rich in the pleiotropic cytokine IL-10, which can be produced by both tumor cells and macrophages, and that IL-10-activated human macrophages have enhanced capacity to engulf apoptotic cells in vitro. This was found to be dependent on the macrophage tethering receptor of apoptotic cells, CD14. Furthermore, IL-10-activated macrophages were found to produce markedly higher levels of the B cell survival factor, B cell-activating factor of the TNF family/B lymphocyte stimulator (BAFF/BLyS) than macrophages matured in the absence of IL-10. Coculture of macrophages with BL cells further enhanced BAFF secretion. Significantly, we show that enhancement of BL cell survival by IL-10-activated macrophages is mediated by a BAFF-dependent component and that BAFF is produced at high levels by tumor-associated macrophages in situ. These results indicate that macrophages, regulated by IL-10, have the potential to promote BL pathogenesis, first, through suppression of antitumor immunity following enhanced engulfment of apoptotic tumor cells and, second, through increased production of tumor cell growth/survival factors.