Ilsong Institute of Life Science, Hallym University, Anyang, Gyeonggi-do 14066, Korea.
Molecular Regulation of Aging, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan.
Int J Mol Sci. 2017 Oct 27;18(11):2258. doi: 10.3390/ijms18112258.
The conversion of peptidylarginine into peptidylcitrulline by calcium-dependent peptidylarginine deiminases (PADs) has been implicated in the pathogenesis of a number of diseases, identifying PADs as therapeutic targets for various diseases. The PAD inhibitor Cl-amidine ameliorates the disease course, severity, and clinical manifestation in multiple disease models, and it also modulates dendritic cell (DC) functions such as cytokine production, antigen presentation, and T cell proliferation. The beneficial effects of Cl-amidine make it an attractive compound for PAD-targeting therapeutic strategies in inflammatory diseases. Here, we found that Cl-amidine inhibited nitric oxide (NO) generation in a time- and dose-dependent manner in maturing DCs activated by lipopolysaccharide (LPS). This suppression of NO generation was independent of changes in NO synthase (NOS) enzyme activity levels but was instead dependent on changes in inducible NO synthase (iNOS) transcription and expression levels. Several upstream signaling pathways for iNOS expression, including the mitogen-activated protein kinase, nuclear factor-κB p65 (NF-κB p65), and hypoxia-inducible factor 1 pathways, were not affected by Cl-amidine. By contrast, the LPS-induced signal transducer and the activator of transcription (STAT) phosphorylation and activator protein-1 (AP-1) transcriptional activities (c-Fos, JunD, and phosphorylated c-Jun) were decreased in Cl-amidine-treated DCs. Inhibition of Janus kinase/STAT signaling dramatically suppressed iNOS expression and NO production, whereas AP-1 inhibition had no effect. These results indicate that Cl-amidine-inhibited STAT activation may suppress iNOS expression. Additionally, we found mildly reduced cyclooxygenase-2 expression and prostaglandin E2 production in Cl-amidine-treated DCs. Our findings indicate that Cl-amidine acts as a novel suppressor of iNOS expression, suggesting that Cl-amidine has the potential to ameliorate the effects of excessive iNOS/NO-linked immune responses.
钙依赖性肽基精氨酸脱亚氨酶（PADs）将肽基精氨酸转化为肽基瓜氨酸，这与许多疾病的发病机制有关，鉴定 PADs 为各种疾病的治疗靶点。PAD 抑制剂 Cl-amidine 可改善多种疾病模型的疾病进程、严重程度和临床表现，还可调节树突状细胞（DC）的功能，如细胞因子产生、抗原呈递和 T 细胞增殖。Cl-amidine 的有益作用使其成为炎症性疾病中针对 PAD 的治疗策略的有吸引力的化合物。在这里，我们发现 Cl-amidine 以时间和剂量依赖的方式抑制脂多糖（LPS）激活的成熟 DC 中一氧化氮（NO）的产生。这种对 NO 生成的抑制与一氧化氮合酶（NOS）酶活性水平的变化无关，而是依赖于诱导型一氧化氮合酶（iNOS）转录和表达水平的变化。几种 iNOS 表达的上游信号通路，包括丝裂原活化蛋白激酶、核因子-κB p65（NF-κB p65）和缺氧诱导因子 1 途径，不受 Cl-amidine 影响。相比之下，Cl-amidine 处理的 DC 中 LPS 诱导的信号转导和转录激活因子（STAT）磷酸化和激活蛋白-1（AP-1）转录活性（c-Fos、JunD 和磷酸化 c-Jun）降低。Janus 激酶/STAT 信号抑制显著抑制 iNOS 表达和 NO 产生，而 AP-1 抑制没有作用。这些结果表明，Cl-amidine 抑制的 STAT 激活可能抑制 iNOS 表达。此外，我们发现 Cl-amidine 处理的 DC 中环氧合酶-2 表达和前列腺素 E2 产生略有降低。我们的研究结果表明，Cl-amidine 作为 iNOS 表达的新型抑制剂发挥作用，表明 Cl-amidine 具有减轻过度的 iNOS/NO 相关免疫反应的潜力。
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