Vijay-Kumar Matam, Wu Huixia, Aitken Jesse, Kolachala Vasantha L, Neish Andrew S, Sitaraman Shanthi V, Gewirtz Andrew T
Department of Pathology and Laboratory Medicine, Epithelial Pathobiology Unit, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Inflamm Bowel Dis. 2007 Jul;13(7):856-64. doi: 10.1002/ibd.20142.
Mimetics of bacterial DNA, given orally or subcutaneously, protect mice from experimental colitis via a toll-like receptor (TLR)-9-dependent mechanism. The goal of the study was to define whether synthetic viral RNA, polyinosinic acid:cytidylic acid [poly(I:C)], which is also a potent immunomodulator, might also affect murine colitis and, if so, define whether such effects were mediated by TLR3, which is one of at least 4 known receptors for this viral RNA analog.
Mice (C57BL6, IL-10KO, or TLR3 KO) were administered 1.5% dextran sodium sulfate (DSS) in drinking water for 7 days. Two hours before treatment with DSS, mice were given phosphate-buffered saline (PBS) or poly(I:C) 20 mug subcutaneously (s.c.), or 100 mug intragastrically (i.g.).
In wildtype mice s.c. administration of poly(I:C) dramatically protected against DSS-induced colitis as assessed by every parameter analyzed, which included body weight, rectal bleeding, colonic myeloperoxidase, histopathology, serum keratinocyte-derived chemokine, serum amyloid A, and lipocalin-2. In contrast, i.g. administration of poly(I:C) offered no protection in this colitis model nor did its administration activate the innate immune system as assessed by serologic parameters. Subcutaneous poly(I:C) protected against DSS-induced colitis equally well in C57BL6 and IL-10KO mice, indicating that this antiinflammatory cytokine is not required for such protection. Protection against colitis given by poly(I:C) treatment was ablated in TLR3 KO, indicating that the protective action of this viral RNA analog was mediated by this receptor.
Activation of TLR3 on cells that are accessible by systemic, but not oral, administration of synthetic viral RNA results in protection against the acute inflammation that can ensue upon damage of the gut epithelium. Thus, this viral RNA analog, which is under clinical trials for other inflammatory disorders (e.g., lupus), may also have therapeutic value for inflammatory bowel disease.
口服或皮下给予细菌DNA模拟物，可通过Toll样受体（TLR）-9依赖性机制保护小鼠免受实验性结肠炎的侵害。本研究的目的是确定同样作为一种强效免疫调节剂的合成病毒RNA聚肌苷酸:胞苷酸[poly（I:C）]是否也会影响小鼠结肠炎，如果是，确定这种作用是否由TLR3介导，TLR3是这种病毒RNA类似物至少4种已知受体之一。
给小鼠（C57BL6、IL-10基因敲除小鼠或TLR3基因敲除小鼠）饮用含1.5%葡聚糖硫酸钠（DSS）的水7天。在用DSS治疗前两小时，给小鼠皮下注射（s.c.）20μg磷酸盐缓冲盐水（PBS）或聚肌苷酸:胞苷酸，或胃内给予（i.g.）100μg。
在野生型小鼠中，皮下注射聚肌苷酸:胞苷酸通过所分析的各项参数（包括体重、直肠出血、结肠髓过氧化物酶、组织病理学、血清角质形成细胞衍生趋化因子、血清淀粉样蛋白A和脂质运载蛋白-2）评估，显著保护小鼠免受DSS诱导的结肠炎。相比之下，在该结肠炎模型中，胃内给予聚肌苷酸:胞苷酸没有提供保护作用，且根据血清学参数评估，其给予也未激活先天免疫系统。皮下注射聚肌苷酸:胞苷酸在C57BL6和IL-10基因敲除小鼠中对DSS诱导的结肠炎的保护效果相同，表明这种抗炎细胞因子并非这种保护作用所必需。聚肌苷酸:胞苷酸治疗对结肠炎的保护作用在TLR3基因敲除小鼠中消失，表明这种病毒RNA类似物的保护作用是由该受体介导的。
全身给药而非口服给予合成病毒RNA可接触到的细胞上TLR3的激活，可保护小鼠免受肠道上皮损伤后可能随之发生的急性炎症。因此，这种正在进行其他炎症性疾病（如狼疮）临床试验的病毒RNA类似物，可能对炎症性肠病也具有治疗价值。
