Xu Jing, Peng Wen-Rui, Zhang Die, Sun Hong-Xin, Li Lei, Sun Fan, Gu Zhi-Chun, Lin Hou-Wen
School of Medicine, Tongji University, Shanghai 200092, People's Republic of China; Research Center for Marine Drugs, Department of Pharmacy, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, People's Republic of China.
Research Center for Marine Drugs, Department of Pharmacy, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, People's Republic of China; School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, People's Republic of China.
Int Immunopharmacol. 2024 Mar 10;129:111576. doi: 10.1016/j.intimp.2024.111576. Epub 2024 Feb 13.
Cyanogramide (AC14), a novel alkaloid, isolated from the fermentation broth of the marine-derived Actinoalloteichus cyanogriseus. However, the exact role of AC14 in inflammatory bowel disease (IBD) is poorly understood. Our results demonstrated that AC14 exhibited significant inhibition of IL-6 release in THP-1 cells and a "Caco-2/THP-1" coculture system after stimulation with LPS for 24 h. However, no significant effect on TNF-α production was observed. Furthermore, in 2.5 % DSS-induced colitis mice, AC14 treatment led to improvement in body weight, colon length, and intestine mucosal barrier integrity. AC14 also suppressed serum IL-6 production and modulated dysregulated microbiota in the mice. Mechanistically, AC14 was found to inhibit the phosphorylation of Janus kinase (JAK) 2 and signal transducers and activators of transcription (STAT) 3, while simultaneously elevating the expression of suppressor of cytokine signaling (SOCS) 3, both in vivo and in vitro. These findings suggest that AC14 exerts its suppressive effects on IL-6 production in DSS-induced IBD mice through the JAK2-STAT3-SOCS3 signaling pathway. Our study highlights the potential of AC14 as a therapeutic agent for the treatment of IBD.
氰胍胺（AC14）是一种从海洋来源的蓝灰放线多孢菌发酵液中分离出的新型生物碱。然而，AC14在炎症性肠病（IBD）中的确切作用尚不清楚。我们的结果表明，在脂多糖（LPS）刺激24小时后，AC14在THP-1细胞和“Caco-2/THP-1”共培养系统中对白细胞介素-6（IL-6）的释放表现出显著抑制作用。然而，未观察到对肿瘤坏死因子-α（TNF-α）产生有显著影响。此外，在2.5%葡聚糖硫酸钠（DSS）诱导的结肠炎小鼠中，AC14治疗导致体重、结肠长度和肠黏膜屏障完整性得到改善。AC14还抑制了小鼠血清中IL-6的产生，并调节了失调的微生物群。从机制上讲，发现AC14在体内和体外均能抑制Janus激酶（JAK）2和信号转导及转录激活因子（STAT）3的磷酸化，同时提高细胞因子信号抑制因子（SOCS）3的表达。这些发现表明，AC14通过JAK2-STAT3-SOCS3信号通路对DSS诱导的IBD小鼠中IL-6的产生发挥抑制作用。我们的研究突出了AC14作为治疗IBD的治疗剂的潜力。
