Department of Immunology, University of Regensburg, 93053 Regensburg, Germany.
J Immunol. 2012 May 15;188(10):4931-9. doi: 10.4049/jimmunol.1102442. Epub 2012 Apr 13.
β-Defensins are known for their antimicrobial activity and belong to the molecular barrier of the innate immune system against invading pathogens. In addition, it has been shown that some members of the β-defensin superfamily have the capacity to promote local innate inflammatory and systemic adaptive immune responses, mediated in part by the interaction with CCR6. We found that mouse β-defensin 14 (mBD14, Defb14), a newly identified member of the mouse β-defensin superfamily, is expressed in mouse fibrosarcoma tumor tissue. Tumor cells overexpressing mBD14 demonstrated enhanced solid tumor growth in syngeneic C57BL/6 mice concomitant with increased vascularization of these tumors. Furthermore, mBD14-overexpressing tumors demonstrated increased expression of proangiogenic MIP-2 (CXCL2) ex vivo. In contrast, vascular endothelial growth factor expression was not affected. Cellular analysis of tumor-infiltrating leukocytes revealed a significant increase of CCR6(+) B220(+) lymphocytes in solid tumors derived from mBD14-overexpressing tumor cells. Enhanced tumor growth of mBD14-overexpressing fibrosarcomas was abolished in CCR6-deficient mice, which was paralleled by decreased infiltration of CCR6(+) B220(+) lymphocytes, indicating the requirement of CCR6 expression on host cells. Previously, the interaction of activated, LTαβ(+), lymphocytes with lymphotoxin β-receptor-expressing fibrosarcoma tumor cells has been identified as a new CXCL2-dependent proangiogenic pathway. Coexpression of a soluble lymphotoxin β-receptor:Ig fusion protein, an inhibitor of CXCL2-dependent angiogenesis, in mBD14-overexpressing fibrosarcoma tumor cells abolished enhanced solid tumor growth. Thus, we conclude that mBD14 expression by tumor-infiltrating host cells results in the chemoattraction of CCR6(+) B220(+) lymphocytes, which in turn initiates a proangiogenic pathway leading to enhanced angiogenesis and organized tumor tissue development.
β-防御素因其抗菌活性而闻名，属于先天免疫系统抵抗入侵病原体的分子屏障。此外，已经表明β-防御素超家族的一些成员具有促进局部先天炎症和全身适应性免疫反应的能力，部分是通过与 CCR6 的相互作用介导的。我们发现，小鼠β-防御素 14（mBD14，Defb14），是小鼠β-防御素超家族的新成员，在小鼠纤维肉瘤肿瘤组织中表达。过表达 mBD14 的肿瘤细胞在同基因 C57BL/6 小鼠中表现出增强的实体瘤生长，同时这些肿瘤的血管生成增加。此外，过表达 mBD14 的肿瘤表现出体外表达增加的促血管生成 MIP-2（CXCL2）。相比之下，血管内皮生长因子的表达不受影响。肿瘤浸润白细胞的细胞分析显示，过表达 mBD14 的肿瘤细胞来源的实体瘤中，CCR6（+）B220（+）淋巴细胞显著增加。CCR6 缺陷型小鼠中过表达 mBD14 的纤维肉瘤的增强肿瘤生长被消除，这与 CCR6（+）B220（+）淋巴细胞浸润减少平行，表明宿主细胞上 CCR6 的表达是必需的。先前，已鉴定出激活的、LTαβ（+）淋巴细胞与表达淋巴毒素 β 受体的纤维肉瘤肿瘤细胞之间的相互作用是一种新的 CXCL2 依赖性促血管生成途径。在过表达 mBD14 的纤维肉瘤肿瘤细胞中共同表达可溶性淋巴毒素 β 受体：Ig 融合蛋白，一种 CXCL2 依赖性血管生成抑制剂，可消除增强的实体瘤生长。因此，我们得出结论，肿瘤浸润宿主细胞表达 mBD14 导致 CCR6（+）B220（+）淋巴细胞的趋化作用，进而启动促血管生成途径，导致血管生成增强和组织化肿瘤组织的发展。
