Imai Masaki, Hwang Hee-Young, Norris James S, Tomlinson Stephen
Department of Microbiology and Immunology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA.
Immunology. 2004 Mar;111(3):291-7. doi: 10.1111/j.0019-2805.2004.01815.x.
Dexamethasone has been shown to up-regulate human mucin 1 (MUC1) expression in certain types of cancer cell lines in vitro, suggesting that this gluocorticoid may enhance MUC1-based immunotherapies. Here we investigated the effect of dexamethasone on MUC1 expression in the DU145 human prostate cancer cell line in terms of antibody-mediated complement-dependent cell lysis. Cells treated with 1 x 10-8 m dexamethasone in vitro expressed maximal levels of MUC1 after 6 days, with an approximately 3-fold increase over MUC1 levels on untreated cells. DU145 cells were highly resistant to lysis by anti-MUC1 antibody and complement, and their susceptibility to antibody and complement was unaffected by dexamethasone treatment. However, dexamethasone also induced expression of the complement inhibitor decay accelerating factor (DAF) on DU145 cells. Blocking or overcoming the function of DAF resulted in enhanced complement-dependent lysis of dexamethasone-treated cells with anti-MUC1 antibodies, indicating that the failure of dexamethasone to enhance the complement susceptibility of DU145 cells was caused by the up-regulated expression of DAF. We also investigated MUC1 expression in vivo and found that MUC1 expression was significantly up-regulated on tumour cells isolated from immune-deficient mice that had been injected with dexamethasone. However, in contrast to in vitro data, there was no difference between the levels of DAF expressed on tumour-derived DU145 cells isolated from either phosphate buffered saline (PBS)-treated or dexamethasone-treated mice, and tumour cells isolated from dexamethasone-treated mice were more sensitive to complement-mediated lysis. In the broad context of immunotherapy, the in vivo data support the use of dexamethasone as an adjunct treatment. Up-regulated DAF expression would not be a favourable outcome of dexamethasone treatment in terms of complement-dependent antibody therapy, but the in vivo data caution against extrapolation of in vitro data with regard to the modulation of complement inhibitors reported here and elsewhere.
地塞米松已被证明在体外可上调某些类型癌细胞系中的人黏蛋白1（MUC1）表达，这表明这种糖皮质激素可能会增强基于MUC1的免疫疗法。在此，我们从抗体介导的补体依赖性细胞裂解方面研究了地塞米松对DU145人前列腺癌细胞系中MUC1表达的影响。体外经1×10⁻⁸ M地塞米松处理的细胞在6天后表达MUC1的水平最高，比未处理细胞的MUC1水平增加了约3倍。DU145细胞对抗MUC1抗体和补体的裂解具有高度抗性，其对抗体和补体的敏感性不受地塞米松处理的影响。然而，地塞米松也诱导DU145细胞上补体抑制剂衰变加速因子（DAF）的表达。阻断或克服DAF的功能导致用地塞米松处理的细胞与抗MUC1抗体的补体依赖性裂解增强，这表明地塞米松未能增强DU145细胞对补体的敏感性是由DAF表达上调所致。我们还研究了体内的MUC1表达，发现从注射了地塞米松的免疫缺陷小鼠分离的肿瘤细胞上MUC1表达明显上调。然而，与体外数据相反，从磷酸盐缓冲盐水（PBS）处理或地塞米松处理的小鼠分离的肿瘤来源DU145细胞上表达的DAF水平没有差异，并且从地塞米松处理的小鼠分离的肿瘤细胞对补体介导的裂解更敏感。在免疫疗法的广泛背景下，体内数据支持将地塞米松用作辅助治疗。就补体依赖性抗体治疗而言，DAF表达上调并非地塞米松治疗的有利结果，但体内数据提醒不要外推此处及其他地方报道的关于补体抑制剂调节的体外数据。
