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首页> 外文期刊>Canadian Journal of Physiology and Pharmacology >Lysosomotropic drugs inhibit maturation of transforming growth factor-beta.
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Lysosomotropic drugs inhibit maturation of transforming growth factor-beta.

机译：溶同溶性药物抑制转化生长因子-β的成熟。

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摘要

Transforming growth factor-beta (TGFbeta) is synthesized as a precursor protein, pro-TGFbeta, that must be cleaved by a furin-like proteinase before it becomes biologically active. We hypothesized that alkalinization of the trans-Golgi network (TGN)/endosome system may suppress pro-TGFbeta processing and decrease TGFbeta secretion. This hypothesis was tested in human A549 alveolar epithelial and T98G glioblastoma cell lines and in C57BL/6 mice. Inhibition of furin-like activity with decanoyl-RVKR chloromethylketone suppressed pro-TGFbeta processing, thereby significantly reducing the levels of secreted TGFbeta. Brefeldin A, bafilomycin A1, ammonium chloride, and monensin also prevented pro-TGFbeta processing. The alkalinizing lysosomotropic drugs chloroquine, hydroxychloroquine, amodiaquine, and azithromycin had a similar effect on the overall production of mature bioactive TGFbeta. Reduced levels of secreted TGFbeta were also associated with a decrease in Smad2 signaling. Mice treated with chloroquineshowed a decrease in bronchoalveolar lavage fluid TGFbeta. We conclude that alkalinizing lysosomotropic drugs inhibit pro-TGFbeta processing.
机译：转化生长因子-β（TGFbeta）是作为前体蛋白，pro-TGFbeta合成的，必须先被弗林蛋白酶样蛋白酶裂解才能使其具有生物活性。我们假设反式高尔基体网络（TGN）/内体系统的碱化可以抑制促TGFbeta加工并减少TGFbeta的分泌。在人类A549肺泡上皮细胞和T98G胶质母细胞瘤细胞系以及C57BL / 6小鼠中测试了该假设。用癸酰基-RVKR氯甲基酮抑制弗林蛋白酶样活性可抑制pro-TGFbeta加工，从而显着降低分泌的TGFbeta的水平。布雷菲德菌素A，bafilomycin A1，氯化铵和莫能菌素也阻止了促TGFbeta的加工。碱化溶溶同质药物氯喹，羟氯喹，阿莫地喹和阿奇霉素对成熟的生物活性TGFbeta的整体生产具有类似的影响。分泌的TGFβ水平降低还与Smad2信号转导降低有关。用氯喹治疗的小鼠显示支气管肺泡灌洗液TGFbeta降低。我们得出结论，碱化溶溶同质药物可抑制促TGFbeta的加工。

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