Gliotoxin

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]。