Processing of immunosuppressive pro-TGF-β1,2 by human glioblastoma cells involves cytoplasmic and secreted furin-like proteases

被引:91
作者
Leitlein, J
Aulwurm, S
Waltereit, R
Naumann, U
Wagenknecht, B
Garten, W
Weller, M
Platten, M
机构
[1] Univ Tubingen, Sch Med, Dept Neurol, Lab Mol Neurooncol, D-72076 Tubingen, Germany
[2] Univ Marburg, Inst Virol, D-3550 Marburg, Germany
关键词
D O I
10.4049/jimmunol.166.12.7238
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
TGF-beta is a putative mediator of immunosuppression associated with malignant glioma and other types of cancer. Subtilisin-like proprotein convertases such as furin are thought to mediate TGF-beta processing. Here we report that human malignant glioma cell lines express furin mRNA and protein, exhibit furin-like protease (FLP) activity, and release active furin into the cell culture supernatant. FLP activity is not modulated by exogenous TGF-beta or neutralizing TGF-beta Abs. Exposure of LN-18 and T98G glioma cell lines to the furin inhibitor, decanoyl-Arg-Val-Lys-Arg-chloromethylketone, inhibits processing of the TGF-beta1 and TGF-beta2 precursor molecules and, consequently, the release of mature bioactive TGF-beta molecules. Ectopic expression of PDX, a synthetic antitrypsin analog with antifurin activity, in the glioma cells inhibits FLP activity, TGF-beta processing, and TGF-beta release. Thus, subtilisin-like proprotein convertases may represent a novel target for the immunotherapy of malignant glioma and other cancers or pathological conditions characterized by enhanced TGF-beta bioactivity.
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收藏
页码:7238 / 7243
页数:6
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