Nematode Asparaginyl-tRNA Synthetase Resolves Intestinal Inflammation in Mice with T-Cell Transfer Colitis
Nematode Asparaginyl-tRNA Synthetase Resolves Intestinal Inflammation in Mice with T-Cell Transfer Colitis
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DOI：
10.1128/cvi.00594-12
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发表时间：
2013-02-01
影响因子：
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通讯作者：
Elliott, David
中科院分区：
文献类型：
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作者：
Kron, Michael A.;Metwali, Ahmed;Elliott, David
控制寄生线虫感染对炎症性肠病（IBD）病程的治疗作用已在动物和人类模型中得到证实。然而，个别特征良好的线虫蛋白无法重建这些有益的效果，限制了组分免疫疗法在人类疾病中的应用。引起慢性人类淋巴丝虫病的线虫，马来丝虫和班氏吴策线虫，是引起免疫抑制的寄生虫之一。已显示丝虫性淋巴病理学涉及NF-κ B途径依赖性的血管内皮生长因子（VEGF）的产生，并且还报道了通过NF-κ B途径由白细胞介素8（IL-8）刺激VEGF表达。以前，我们已经表明，丝虫天冬酰胺酰-tRNA合成酶（rBmAsnRS）与IL-8受体的相互作用，使用的细胞外环的组合，不同于IL-8结合。为了验证rBmAsnRS可能在体内诱导抗炎作用的假设，我们使用T细胞转移小鼠研究了rBmAsnRS在建立的小鼠结肠炎模型中的作用。用100 μ g rBmAsnRS在2周内腹腔内处理4次的T细胞转移结肠炎小鼠显示结肠粘膜中的细胞浸润消退，沿着诱导CD 8（+）细胞应答。此外，rBmAsnRS诱导CD 3（+）和脂多糖（LPS）和胞嘧啶磷酸鸟苷（CPG）刺激的脾细胞产生IL-10。总之，这项工作证明了一种新的抗炎线虫蛋白，支持卫生假说，并支持继续改进用于治疗IBD的替代免疫疗法。
The therapeutic effects of a controlled parasitic nematode infection on the course of inflammatory bowel disease (IBD) have been demonstrated in both animal and human models. However, the inability of individual well-characterized nematode proteins to recreate these beneficial effects has limited the application of component immunotherapy to human disease. The nematodes that cause chronic human lymphatic filariasis, Brugia malayi and Wuchereria bancrofti, are among the parasites that induce immune suppression. Filarial lymphatic pathology has been shown to involve NF-kappa B pathway-dependent production of vascular endothelial growth factor (VEGF), and stimulation of VEGF expression has also been reported by interleukin 8 (IL-8) via NF-kappa B pathways. Previously, we have shown that the filarial asparaginyl-tRNA synthetase (rBmAsnRS) interacts with IL-8 receptors using a combination of extracellular loops that differ from those bound by IL-8. To test the hypothesis that rBmAsnRS might induce an anti-inflammatory effect in vivo, we studied the effects of rBmAsnRS in an established murine colitis model using T-cell transfer mice. T-cell transfer colitis mice treated intraperitoneally with 100 mu g of rBmAsnRS four times over 2 weeks showed resolution of cellular infiltration in the colonic mucosa, along with induction of a CD8(+) cellular response. In addition, rBmAsnRS induced a rise in IL-10 production from CD3(+) and lipopolysaccharide (LPS)- and cytosine phosphate guanosine (CPG)-stimulated splenic cells. In summary, this work demonstrates a novel anti-inflammatory nematode protein, supports the hygiene hypothesis, and supports continued refinement of alternative immunotherapies for treatment of IBD.