Ogden Carol Anne, Pound John D, Batth Balvinder K, Owens Sarah, Johannessen Ingolfur, Wood Katrina, Gregory Christopher D
Centre for Inflammation Research, University of Edinburgh College of Medicine and Veterinary Medicine, Edinburgh, United Kingdom.
J Immunol. 2005 Mar 1;174(5):3015-23. doi: 10.4049/jimmunol.174.5.3015.
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.
伯基特淋巴瘤（BL）的特点是肿瘤细胞频繁凋亡以及巨噬细胞大量浸润。由于BL细胞具有以高比率进行凋亡的内在倾向，我们推断BL中的巨噬细胞在至少两种对肿瘤发病机制有影响的活动中功能增强：1）吞噬凋亡细胞，这是一种已知可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，我们表明BL的微环境富含多效性细胞因子白细胞介素-10（IL-10），它可由肿瘤细胞和巨噬细胞产生，并且IL-10激活的人巨噬细胞在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拴系受体CD14。此外，发现IL-10激活的巨噬细胞产生的肿瘤坏死因子家族B细胞活化因子/ B淋巴细胞刺激因子（BAFF/BLyS）水平明显高于在无IL-10情况下成熟的巨噬细胞。巨噬细胞与BL细胞共培养进一步增强了BAFF分泌。重要的是，我们表明IL-10激活的巨噬细胞对BL细胞存活的增强作用是由BAFF依赖性成分介导的，并且BAFF在原位肿瘤相关巨噬细胞中高水平产生。这些结果表明，受IL-10调节的巨噬细胞有可能促进BL发病机制，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/存活因子的产生。
