title: Nematode asparaginyl-tRNA synthetase resolves intestinal inflammation in mice with T-cell transfer colitis.
abstract: 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-κB 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-κB 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 μg 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.
authors.affiliation: Department of Medicine, Biotechnology and Bioengineering Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA. mkron@mcw.edu
authors.forename: Michael A
authors.initials: MA
authors.lastname: Kron
authors.forename: Ahmed
authors.initials: A
authors.lastname: Metwali
authors.forename: Sanja
authors.initials: S
authors.lastname: Vodanovic-Jankovic
authors.forename: David
authors.initials: D
authors.lastname: Elliott
mesh_terms: D000818:Animals; D001226:Aspartate-tRNA Ligase / Q000096:biosynthesis / Q000276:immunology* / Q000378:metabolism; D017178:Brugia malayi / Q000201:enzymology* / Q000276:immunology; D017252:CD3 Complex / Q000096:biosynthesis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003092:Colitis / Q000139:chemically induced / Q000276:immunology / Q000628:therapy*; D003713:Dendritic Cells; D018398:Homeodomain Proteins / Q000235:genetics; D007167:Immunotherapy; D007249:Inflammation; D018836:Inflammation Mediators; D016753:Interleukin-10 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D007413:Intestinal Mucosa / Q000276:immunology / Q000473:pathology; D007422:Intestines / Q000276:immunology* / Q000469:parasitology*; D008070:Lipopolysaccharides; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D010894:Piroxicam; D012346:RNA, Transfer, Amino Acyl / Q000096:biosynthesis / Q000276:immunology* / Q000378:metabolism; D053700:Receptors, Interleukin-8 / Q000378:metabolism; D042442:Vascular Endothelial Growth Factors / Q000096:biosynthesis; D014958:Wuchereria bancrofti / Q000201:enzymology* / Q000276:immunology
chemical_list: D017252:CD3 Complex; D018398:Homeodomain Proteins; D018836:Inflammation Mediators; D016209:Interleukin-8; D008070:Lipopolysaccharides; D016328:NF-kappa B; D012346:RNA, Transfer, Amino Acyl; D053700:Receptors, Interleukin-8; D042442:Vascular Endothelial Growth Factors; C064658:RAG-1 protein; D016753:Interleukin-10; D010894:Piroxicam; D001226:Aspartate-tRNA Ligase; C029194:asparaginyl-tRNA synthetase