Department of Pathology and Laboratory Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.
Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.
Physiol Genomics. 2019 Dec 1;51(12):657-667. doi: 10.1152/physiolgenomics.00066.2019. Epub 2019 Nov 25.
Rhesus theta defensin-1 (RTD-1), a macrocyclic immunomodulatory host defense peptide from Old World monkeys, is therapeutic in pristane-induced arthritis (PIA) in rats, a model of rheumatoid arthritis (RA). RNA-sequence (RNA-Seq) analysis was used to interrogate the changes in gene expression in PIA rats, which identified 617 differentially expressed genes (DEGs) in PIA synovial tissue of diseased rats. Upstream regulator analysis showed upregulation of gene expression pathways regulated by TNF, IL1B, IL6, proinflammatory cytokines, and matrix metalloproteases (MMPs) involved in RA. In contrast, ligand-dependent nuclear receptors like the liver X-receptors NR1H2 and NR1H3 and peroxisome proliferator-activated receptor gamma (PPARG) were downregulated in arthritic synovia. Daily RTD-1 treatment of PIA rats for 1-5 days following disease presentation modulated 340 of the 617 disease genes, and synovial gene expression in PIA rats treated 5 days with RTD-1 closely resembled the gene signature of naive synovium. Systemic RTD-1 inhibited proinflammatory upstream regulators such as TNF, IL1, and IL6 and activated antiarthritic ligand-dependent nuclear receptor pathways, including PPARG, NR1H2, and NR1H3, that were suppressed in untreated PIA rats. RTD-1 also inhibited proinflammatory responses in IL-1β-stimulated human RA fibroblast-like synoviocytes (FLS) in vitro and diminished expression of human orthologs of disease genes that are induced in rat PIA synovium. Thus, the antiarthritic mechanisms of systemic RTD-1 include homeostatic regulation of arthritogenic gene networks in a manner that correlates temporally with clinical resolution of rat PIA.
恒河猴θ防御素-1（RTD-1）是一种来自旧世界猴的大环免疫调节宿主防御肽，对大鼠诱导性关节炎（PIA）具有治疗作用，PIA 是类风湿关节炎（RA）的模型。RNA 测序（RNA-Seq）分析用于研究 PIA 大鼠基因表达的变化，该分析在患病大鼠的 PIA 滑膜组织中鉴定出 617 个差异表达基因（DEGs）。上游调节剂分析显示，参与 RA 的 TNF、IL1B、IL6、促炎细胞因子和基质金属蛋白酶（MMPs）调节的基因表达途径上调。相比之下，配体依赖性核受体，如肝 X 受体 NR1H2 和 NR1H3 以及过氧化物酶体增殖物激活受体γ（PPARG），在关节炎滑膜中下调。在疾病发生后 1-5 天内，每天给予 RTD-1 治疗 PIA 大鼠，可调节 617 个疾病基因中的 340 个，并且用 RTD-1 治疗 5 天的 PIA 大鼠的滑膜基因表达与幼稚滑膜的基因特征非常相似。全身性 RTD-1 抑制了促炎上游调节剂，如 TNF、IL1 和 IL6，并激活了抗关节炎配体依赖性核受体途径，包括 PPARG、NR1H2 和 NR1H3，这些途径在未经治疗的 PIA 大鼠中受到抑制。RTD-1 还抑制了体外 IL-1β 刺激的人 RA 成纤维样滑膜细胞（FLS）中的促炎反应，并降低了在大鼠 PIA 滑膜中诱导的疾病基因的人类同源物的表达。因此，全身性 RTD-1 的抗关节炎机制包括以与大鼠 PIA 临床缓解时间相关的方式对致关节炎基因网络进行动态调节。
