Inhibition of immunosuppressive effects of melanoma-inhibiting activity (MIA) by antisense techniques
Inhibition of immunosuppressive effects of melanoma-inhibiting activity (MIA) by antisense techniques
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DOI：
10.1002/ijc.20549
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发表时间：
2005-01-01
影响因子：
6.4
通讯作者：
Bogdahn, U
中科院分区：
文献类型：
--
作者：
Jachimczak, P;Apfel, R;Bogdahn, U
黑色素瘤抑制活性（Melanoma inhibitory activity， MIA）是恶性黑色素瘤分泌的一种11kd蛋白。最近的研究发现MIA与包括纤维连接蛋白在内的细胞外基质蛋白的表位相互作用。MIA与alpha4beta1整合素结合位点的结构同源性导致MIA与与alpha4beta1整合素结合的分子发生复杂的相互作用。由于免疫系统细胞表达alpha4beta1整合素（vla4），我们研究了MIA是否可能调节人类白细胞的功能。在此，我们描述MIA对体外培养的MIA阴性胶质瘤细胞系和MIA阳性黑色素瘤细胞系中人pbmc的激活和自身/异体淋巴因子激活杀伤细胞（LAK）细胞毒性的影响。当在有丝分裂原刺激之前加入细胞培养时，MIA以剂量依赖性的方式抑制PHA-或il -2诱导的人PBMC增殖，分别高达63% （H-3-Tdr掺入）和59%（细胞计数）。此外，添加外源性rhMIA （500 ng/ml, f.c）可降低自体（GL和HW）和异体（HTZ-17， HTZ-243和HTZ-374）抗肿瘤LAK细胞毒性。因此，MIA特异性磷酸化反义寡核苷酸对人黑色素瘤细胞中MIA表达的内源性抑制将自身的lak细胞活性提高到与表达MIA反义结构的MIA阴性人HMB黑色素瘤细胞相同的水平。我们的研究结果表明，MIA可能通过抑制细胞抗肿瘤免疫反应而导致恶性黑色素瘤中常见的免疫抑制。利用反义技术拮抗MIA活性可能是治疗恶性黑色素瘤的一种新的治疗策略。(C) 2004 Wiley-Liss, Inc。
Melanoma inhibitory activity (MIA) is an 11 kD protein secreted by malignant melanomas. Recent studies revealed an interaction of MIA with epitopes of extracellular matrix proteins including fibronectin. Structural homology of MIA with the binding sites of alpha4beta1 integrin results in complex interactions of MIA with molecules binding to alpha4beta1 integrin. As cells of the immune system express alpha4beta1 integrins (VLA-4), we investigated whether MIA may modulate the function of human leukocytes. Here we describe the effects of MIA on the activation of human PBMCs and auto-/ allogeneic lymphokine-activated killer cell (LAK) cytotoxicity in human MIA-negative glioma cell lines and MIA-positive melanoma cell lines in vitro. MIA inhibits PHA- or IL-2-induced human PBMC proliferation in a dose-dependent manner up to 63% (H-3-Tdr incorporation) and 59% (cell count), respectively, when added to the cell culture prior to mitogen stimulation. In addition, both autologous (GL and HW) and allogeneic (HTZ-17, HTZ-243 and HTZ-374) antitumor LAK cytotoxicity was reduced by the addition of exogenous rhMIA (500 ng/ml, f.c.). Consequently, endogenous inhibition of MIA expression in human melanoma cells by MIA-specific phosphorothioate antisense oligonucleotides enhanced the autologous LAK-cell activity to the same level as observed in MIA-negative human HMB melanoma cells expressing an MIA-antisense construct. Our results indicate that MIA may contribute to immunosuppression frequently seen in malignant melanomas by inhibiting cellular antitumor immune reactions. Antagonization of MIA activity using antisense techniques may represent a novel therapeutic strategy for treatment of malignant melanomas. (C) 2004 Wiley-Liss, Inc.