Department of Pathology and Laboratory Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
PLoS One. 2012;7(12):e51337. doi: 10.1371/journal.pone.0051337. Epub 2012 Dec 6.
Theta-defensins (θ-defensins) are macrocyclic antimicrobial peptides expressed in leukocytes of Old World monkeys. The peptides are broad spectrum microbicides in vitro and numerous θ-defensin isoforms have been identified in granulocytes of rhesus macaques and Olive baboons. Several mammalian α- and β-defensins, genetically related to θ-defensins, have proinflammatory and immune-activating properties that bridge innate and acquired immunity. In the current study we analyzed the immunoregulatory properties of rhesus θ-defensins 1-5 (RTDs 1-5). RTD-1, the most abundant θ-defensin in macaques, reduced the levels of TNF, IL-1α, IL-1β, IL-6, and IL-8 secreted by blood leukocytes stimulated by several TLR agonists. RTDs 1-5 suppressed levels of soluble TNF released by bacteria- or LPS-stimulated blood leukocytes and THP-1 monocytes. Despite their highly conserved conformation and amino acid sequences, the anti-TNF activities of RTDs 1-5 varied by as much as 10-fold. Systemically administered RTD-1 was non-toxic for BALB/c mice, and escalating intravenous doses were well tolerated and non-immunogenic in adult chimpanzees. The peptide was highly stable in serum and plasma. Single dose administration of RTD-1 at 5 mg/kg significantly improved survival of BALB/c mice with E. coli peritonitis and cecal ligation-and-puncture induced polymicrobial sepsis. Peptide treatment reduced serum levels of several inflammatory cytokines/chemokines in bacteremic animals. Collectively, these results indicate that the anti-inflammatory properties of θ-defensins in vitro and in vivo are mediated by the suppression of numerous proinflammatory cytokines and blockade of TNF release may be a primary effect.
θ-防御素（θ-defensins）是在旧世界猴的白细胞中表达的大环抗菌肽。这些肽在体外具有广谱杀菌作用，并且已经在恒河猴和橄榄狒狒的粒细胞中鉴定出许多 θ-防御素同工型。几种与 θ-防御素在基因上相关的哺乳动物 α-和 β-防御素具有炎症前和免疫激活特性，可将先天免疫和获得性免疫联系起来。在当前的研究中，我们分析了恒河猴 θ-防御素 1-5（RTDs 1-5）的免疫调节特性。RTD-1 是猴中最丰富的 θ-防御素，可降低几种 TLR 激动剂刺激的血液白细胞分泌的 TNF、IL-1α、IL-1β、IL-6 和 IL-8 的水平。RTDs 1-5 抑制了细菌或 LPS 刺激的血液白细胞和 THP-1 单核细胞释放的可溶性 TNF 水平。尽管它们具有高度保守的构象和氨基酸序列，但 RTDs 1-5 的抗 TNF 活性差异可达 10 倍。系统给予 RTD-1 对 BALB/c 小鼠无毒，并且递增的静脉内剂量在成年黑猩猩中耐受良好且无免疫原性。该肽在血清和血浆中高度稳定。RTD-1 单次给药 5mg/kg 可显著提高患有大肠杆菌腹膜炎和盲肠结扎和穿刺诱导的多微生物败血症的 BALB/c 小鼠的存活率。肽治疗可降低菌血症动物的几种炎症细胞因子/趋化因子的血清水平。总之，这些结果表明，θ-防御素在体外和体内的抗炎特性是通过抑制多种促炎细胞因子和阻断 TNF 释放来介导的，而阻断 TNF 释放可能是主要作用。
