Lee Hyun-Su, Yu Jae Sik, Kim Ki Hyun, Jeong Gil-Saeng
College of Pharmacy, Keimyung University, Daegu 42601, Korea.
School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea.
Molecules. 2020 Nov 17;25(22):5374. doi: 10.3390/molecules25225374.
In immunological responses, controlling excessive T cell activity is critical for immunological homeostasis maintenance. Diketoacetonylphenalenone, derived from Hawaiian volcanic soil-associated fungus FT729, possesses moderate anti-inflammatory activity in RAW 264.7 cells but its immunosuppressive effect on T cell activation is unknown. In the present study, diketoacetonylphenalenone (up to 40 μM) did not show cytotoxicity in T cells. Western blot analysis showed treatment with diketoacetonylphenalenone did not alter the expression of anti-apoptotic proteins. Pretreatment with diketoacetonylphenalenone suppressed the interleukin-2 production in activated T cells induced by T cell receptor-mediated stimulation and PMA/A23187. The CFSE-proliferation assay revealed the inhibitory effect of diketoacetonylphenalenone on the proliferation of T cells. The expression of surface molecules on activated T cells was also reduced. We discovered the suppression of the TAK1-IKKα-NF-κB pathway by pretreatment with diketoacetonylphenalenone abrogated mitogen-activated protein kinase (MAPK) signaling in activated T cells. These results suggest that diketoacetonylphenalenone effectively downregulates T cell activity via the MAPK pathway and provides insight into the therapeutic potential of immunosuppressive reagents.
在免疫反应中，控制过度的T细胞活性对于维持免疫稳态至关重要。源自夏威夷火山土壤相关真菌FT729的二酮丙酮基菲烯酮在RAW 264.7细胞中具有中等抗炎活性，但其对T细胞活化的免疫抑制作用尚不清楚。在本研究中，二酮丙酮基菲烯酮（浓度高达40 μM）在T细胞中未显示出细胞毒性。蛋白质印迹分析表明，用二酮丙酮基菲烯酮处理不会改变抗凋亡蛋白的表达。用二酮丙酮基菲烯酮预处理可抑制由T细胞受体介导的刺激以及佛波酯/离子霉素诱导的活化T细胞中白细胞介素-2的产生。羧基荧光素二乙酸琥珀酰亚胺酯增殖试验揭示了二酮丙酮基菲烯酮对T细胞增殖的抑制作用。活化T细胞表面分子的表达也降低了。我们发现，用二酮丙酮基菲烯酮预处理对TAK1-IKKα-NF-κB途径的抑制消除了活化T细胞中的丝裂原活化蛋白激酶（MAPK）信号传导。这些结果表明，二酮丙酮基菲烯酮通过MAPK途径有效下调T细胞活性，并为免疫抑制试剂的治疗潜力提供了见解。
