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.

中文翻译：

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RTD-1 在治疗上使大鼠自身免疫性关节炎的滑膜基因特征正常化，并抑制 RA 滑膜成纤维细胞中的促炎介质。

Rhesus theta defensin-1 (RTD-1) 是一种来自旧大陆猴子的大环免疫调节宿主防御肽，可用于治疗类风湿性关节炎 (RA) 模型大鼠中的 pristane 诱导的关节炎 (PIA)。RNA序列（RNA-Seq）分析用于询问PIA大鼠基因表达的变化，在患病大鼠的PIA滑膜组织中鉴定出617个差异表达基因（DEGs）。上游调节器分析显示由 TNF、IL1B、IL6、促炎细胞因子和参与 RA 的基质金属蛋白酶 (MMP) 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脏 X 受体 NR1H2 和 NR1H3 以及过氧化物酶体增殖物激活受体 γ (PPARG) 在关节炎滑膜中被下调。在疾病出现后每天对 PIA 大鼠进行 1-5 天的 RTD-1 治疗，调节了 617 个疾病基因中的 340 个，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 抑制促炎性上游调节因子，如 TNF、IL1 和 IL6，并激活抗关节炎配体依赖性核受体通路，包括 PPARG、NR1H2 和 NR1H3，这些通路在未经治疗的 PIA 大鼠中受到抑制。RTD-1 还在体外抑制 IL-1β 刺激的人 RA 成纤维细胞样滑膜细胞 (FLS) 的促炎反应，并减少在大鼠 PIA 滑膜中诱导的人类疾病基因直系同源物的表达。因此，