The selective estrogen receptor modulators, tamoxifen and raloxifene, impair dendritic cell differentiation and activation
The selective estrogen receptor modulators, tamoxifen and raloxifene, impair dendritic cell differentiation and activation
复制标题
DOI：
10.4049/jimmunol.175.4.2666
复制
发表时间：
2005-08-15
影响因子：
4.4
通讯作者：
Kovats, S
中科院分区：
文献类型：
--
作者：
Nalbandian, G;Paharkova-Vatchkova, V;Kovats, S
大多数免疫细胞，包括骨髓祖细胞和终末分化的树突状细胞（DC），表达雌激素受体（ER），使这些细胞对雌激素敏感。我们的实验室最近证明，17-β-雌二醇（E2）促进GM-CSF介导的小鼠骨髓前体细胞CD 11 c（+）CD 11b（int）DC的发育。我们测试了治疗选择性雌激素受体调节剂（SERM），雷洛昔芬和他莫昔芬，是否可以扰乱DC的发展和激活。用于治疗乳腺癌和骨质疏松症的SERM与ER结合并介导组织特异性激动或拮抗作用。雷洛昔芬和他莫昔芬抑制分化的雌激素依赖性DC从骨髓前体离体在竞争实验中与生理水平的E2。在SERM存在下分化的DC被评估其内化荧光标记的Ag的能力以及通过增加对APC功能重要的分子的表面表达来响应炎症刺激的能力。虽然SERM暴露的DC表现出增加的能力，内化抗原，他们是低反应的细菌LPS：相对于控制DC，他们不太有效地上调表达的MHC II类，CD 86，并在较小程度上，CD 80和CD 40。这种表型表明，这些SERM通过抑制DC对炎症刺激的反应性来维持DC处于不成熟状态。因此，雷洛昔芬和他莫昔芬损害E2促进的DC分化并降低DC的免疫刺激能力。这些观察结果表明，SERM可能会抑制免疫力时，给予健康个体预防骨质疏松症和乳腺癌，并可能干扰免疫策略，以提高乳腺癌患者的抗肿瘤免疫力。
Most immune cells, including myeloid progenitors and terminally differentiated dendritic cells (DC), express estrogen receptors (ER) making these cells sensitive to estrogens. Our laboratory recently demonstrated that 17-beta-estradiol (E2) promotes the GM-CSF-mediated development of CD11c(+) CD11b(int) DC from murine bone marrow precursors. We tested whether the therapeutic selective estrogen receptor modulators (SERM), raloxifene and tamoxifen, can perturb DC development and activation. SERM, used in treatment of breast cancer and osteoporosis, bind to ER and mediate tissue-specific agonistic or antagonistic effects. Raloxifene and tamoxifen inhibited the differentiation of estrogen-dependent DC from bone marrow precursors ex vivo in competition experiments with physiological levels of E2. DC differentiated in the presence of SERM were assessed for their capacity to internalize fluoresceinated Ags as well as respond to inflammatory stimuli by increasing surface expression of molecules important for APC function. Although SERM-exposed DC exhibited increased ability to internalize Ags, they were hyporesponsive to bacterial LPS: relative to control DC, they less efficiently up-regulated the expression of MHC class II, CD86, and to a lesser extent, CD80 and CD40. This phenotype indicates that these SERM act to maintain DC in an immature state by inhibiting DC responsiveness to inflammatory stimuli. Thus, raloxifene and tamoxifen impair E2-promoted DC differentiation and reduce the immunostimulatory capacity of DC. These observations suggest that SERM may depress immunity when given to healthy individuals for the prevention of osteoporosis and breast cancer and may interfere with immunotherapeutic strategies to improve antitumor immunity in breast cancer patients.