Synergistic activation by p38MAPK and glucocorticoid signaling mediates induction of M2-like tumor-associated macrophages expressing the novel CD20 homolog MS4A8A
Synergistic activation by p38MAPK and glucocorticoid signaling mediates induction of M2-like tumor-associated macrophages expressing the novel CD20 homolog MS4A8A
复制标题
DOI：
10.1002/ijc.25657
复制
发表时间：
2011-07-01
影响因子：
6.4
通讯作者：
Goerdt, Sergij
中科院分区：
文献类型：
--
作者：
Schmieder, Astrid;Schledzewski, Kai;Goerdt, Sergij
肿瘤相关巨噬细胞 (TAM) 代表支持肿瘤生长的交替激活 (M2) 巨噬细胞。之前，我们已经在体外和体内描述了特殊的 LYVE-1(+) M2 TAM 子集；该 TAM 子集的基因分析将 MS4A8A 鉴定为 TAM 在乳腺癌和恶性黑色素瘤体内表达的新型 TAM 分子。在体外，通过结合 M2 介质（IL-4、糖皮质激素）和肿瘤条件培养基 (TCM)，在骨髓源性巨噬细胞 (BMDM) 中强烈诱导 Ms4a8a mRNA 和 MS4A8A 蛋白表达。 MS4A8A(+) TCM/IL-4/GC处理的BMDM混合物显着提高了皮下移植的TS/A乳腺癌的肿瘤生长速率。在强制过度表达 MS4A8A 后，Raw 264.7 巨噬细胞样细胞显示出特殊的基因特征。这些MS4A8A(+) Raw 264.7细胞的混合物也显着提高了皮下移植的乳腺癌的肿瘤生长速率。为了确定参与协同诱导 MS4A8A 的信号通路，分析了 TAM 中具有已知功能的主要信号级联。尽管 NF-κ B 激活抑制剂以及 MAPK JNK 和 ERK 抑制剂没有显示出相关作用，但 p38 α/β MAPK 抑制剂 SB203580 在 mRNA 和蛋白质水平上强烈且高度显着地 (p > 0.001) 抑制 MS4A8A 表达。此外，MS4A8A 的表达在 GC 受体 (GR) 二聚化缺陷的小鼠的 M2 BMDM 中受到限制，表明经典的 GR 基因调控对于 MS4A8A 诱导是必需的。总之，巨噬细胞免疫反应过程中复杂信号整合中 MS4A8A 的表达可能起到微调基因调控的作用。此外，MS4A8A(+) TAM 可能作为选择性癌症治疗的新细胞靶点。
Tumor-associated macrophages (TAMs) represent alternatively activated (M2) macrophages that support tumor growth. Previously, we have described a special LYVE-1(+) M2 TAM subset in vitro and in vivo; gene profiling of this TAM subset identified MS4A8A as a novel TAM molecule expressed in vivo by TAM in mammary carcinoma and malignant melanoma. In vitro, Ms4a8a mRNA and MS4A8A protein expression was strongly induced in bone marrow-derived macrophages (BMDMs) by combining M2 mediators (IL-4, glucocorticoids) and tumor-conditioned media (TCM). Admixture of MS4A8A(+) TCM/IL-4/GC-treated BMDM significantly enhanced the tumor growth rate of subcutaneously transplanted TS/A mammary carcinomas. Upon forced overexpression of MS4A8A, Raw 264.7 macrophage-like cells displayed a special gene signature. Admixture of these MS4A8A(+) Raw 264.7 cells also significantly enhanced the tumor growth rate of subcutaneously transplanted mammary carcinomas. To identify the signaling pathways involved in synergistic induction of MS4A8A, the major signaling cascades with known functions in TAM were analyzed. Although inhibitors of NF-kappa B activation and of the MAPK JNK and ERK did not show relevant effects, the p38 alpha/beta MAPK inhibitor SB203580 strongly and highly significantly (p > 0.001) inhibited MS4A8A expression on mRNA and protein level. In addition, MS4A8A expression was restricted in M2 BMDM from mice with defective GC receptor (GR) dimerization indicating that classical GR gene regulation is mandatory for MS4A8A induction. In conclusion, expression of MS4A8A within the complex signal integration during macrophage immune responses may act to fine tune gene regulation. Furthermore, MS4A8A(+) TAM may serve as a novel cellular target for selective cancer therapy.