Gliotoxin, an immunosuppressive mycotoxin produced by pathogenic strains of Aspergillus and other fungi, is a specific inhibitor of 20S proteasomal chymotrypsin activity with an IC50 of 10μM[1]. Gliotoxin blocks the degradation of IκBα, thereby preventing the activation of NF-κB by inhibiting proteasome activity[2]. Additionally, Gliotoxin inhibits the activity of farnesyltransferase (FTase) and geranylgeranyltransferase I (GGTase I), with IC50 values of 80μM and 17μM, respectively[3]. Gliotoxin can also inhibit phagocytosis by macrophages and the immune functions of other immune cells, and is commonly used in research related to immunology, inflammation, and tumors [4][5].
In vitro, A549 and L132 cells were treated with different concentrations of Gliotoxin (0, 2, 4, 6, 8, 10μM; 24h) caused dose-dependent increase in cytotoxicity and the measured IC50 was 2.7 and 4.25μM. In addition, treatment of A549 and L132 cells with IC50 concentrations of Gliotoxin for 6, 12, and 24 hours resulted a time-dependent increase in reactive oxygen species (ROS) levels[6].
In vivo, exogenous Gliotoxin (1.25ng; 72h; intranasal administration) helped Gliotoxin synthesis deficient strain gliP1 invade into the lung tissue and the lung fungal burden increased markedly in immunosuppressed mice[7].
References:
[1] Kroll, M., Arenzana-Seisdedos, F., Bachelerie, F., Thomas, D., Friguet, B., & Conconi, M. (1999). The secondary fungal metabolite gliotoxin targets proteolytic activities of the proteasome. Chemistry & biology, 6(10), 689–698.
[2] Pahl, H. L., Krauss, B., Schulze-Osthoff, K., Decker, T., Traenckner, E. B., Vogt, M., Myers, C., Parks, T., Warring, P., Mühlbacher, A., Czernilofsky, A. P., & Baeuerle, P. A. (1996). The immunosuppressive fungal metabolite gliotoxin specifically inhibits transcription factor NF-kappaB. The Journal of experimental medicine, 183(4), 1829–1840.
[3] Vigushin, D. M., Mirsaidi, N., Brooke, G., Sun, C., Pace, P., Inman, L., Moody, C. J., & Coombes, R. C. (2004). Gliotoxin is a dual inhibitor of farnesyltransferase and geranylgeranyltransferase I with antitumor activity against breast cancer in vivo. Medical oncology (Northwood, London, England), 21(1), 21–30.
[4] Schlam, D., Canton, J., Carreño, M., Kopinski, H., Freeman, S. A., Grinstein, S., & Fairn, G. D. (2016). Gliotoxin Suppresses Macrophage Immune Function by Subverting Phosphatidylinositol 3,4,5-Trisphosphate Homeostasis. mBio, 7(2), e02242.
[5] Jia, X., Chen, F., Pan, W., Yu, R., Tian, S., Han, G., Fang, H., Wang, S., Zhao, J., Li, X., Zheng, D., Tao, S., Liao, W., Han, X., & Han, L. (2014). Gliotoxin promotes Aspergillus fumigatus internalization into type II human pneumocyte A549 cells by inducing host phospholipase D activation. Microbes and infection, 16(6), 491–501.
[6] Gayathri, L., Akbarsha, M. A., & Ruckmani, K. (2020). In vitro study on aspects of molecular mechanisms underlying invasive aspergillosis caused by gliotoxin and fumagillin, alone and in combination. Scientific reports, 10(1), 14473.
[7] Zhang, C., Chen, F., Liu, X., Han, X., Hu, Y., Su, X., Chen, Y., Sun, Y., & Han, L. (2019). Gliotoxin Induces Cofilin Phosphorylation to Promote Actin Cytoskeleton Dynamics and Internalization of Aspergillus fumigatus Into Type II Human Pneumocyte Cells. Frontiers in microbiology, 10, 1345.
Gliotoxin是一种由病原性曲霉菌等真菌产生的免疫抑制性霉菌毒素，是一种特异性的20S蛋白酶体糜蛋白酶活性抑制剂，IC50为10μM[1]。Gliotoxin通过抑制蛋白酶体的活性，阻断IκBα的降解，进而阻止NF-κB的激活[2]。此外，Gliotoxin还抑制法尼基蛋白转移酶（FTase）和香叶基蛋白转移酶I（GGTase I）的活性，IC50分别为80μM和17μM[3]。Gliotoxin也能够抑制巨噬细胞的吞噬作用及其他免疫细胞的免疫功能,通常用于免疫学、炎症反应以及肿瘤相关研究[4][5]。
在体外，分别用不同浓度的Gliotoxin（0、2、4、6、8、10μM；处理24小时）处理A549和L132细胞后，细胞毒性呈剂量依赖性增加，测得的IC50值分别为2.7μM和4.25μM。此外，用IC50浓度的Gliotoxin处理A549和L132细胞6小时、12小时和24小时后，细胞中的活性氧（ROS）水平呈时间依赖性增加[6]。
在体内，免疫抑制小鼠中，外源性给药Gliotoxin（1.25ng；鼻内给药；72小时）帮助Gliotoxin合成缺陷菌株gliP1侵入肺组织，并显著增加了肺部真菌负荷[7]。