VEGF164 isoform specific regulation of T-cell-dependent experimental colitis in mice
| Autor: | Christopher G. Kevil, Christopher B. Pattillo, John D. Glawe, John H. Chidlow, Songlin Zhang, Sibile Pardue |
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| Rok vydání: | 2011 |
| Předmět: |
CD4-Positive T-Lymphocytes
Vascular Endothelial Growth Factor A Colon Angiogenesis Enzyme-Linked Immunosorbent Assay Mice Transgenic Inflammation Disease T-Lymphocytes Regulatory Inflammatory bowel disease Article Neovascularization Mice medicine Animals Humans Protein Isoforms Immunology and Allergy Colitis Homeodomain Proteins Neovascularization Pathologic business.industry Gastroenterology Aptamers Nucleotide medicine.disease Ulcerative colitis digestive system diseases Mice Inbred C57BL Disease Models Animal Vascular endothelial growth factor A Immunology Leukocyte Common Antigens medicine.symptom business |
| Zdroj: | Inflammatory Bowel Diseases. 17:1501-1512 |
| ISSN: | 1078-0998 |
| DOI: | 10.1002/ibd.21525 |
| Popis: | Inflammatory bowel disease (IBD) consists of Crohn's disease (CD) and ulcerative colitis (UC), two widespread diseases of unknown, multifactorial etiology. Colitis pathology involves a pathological angiogenic response where increases in vascular density participate in colitis histopathology. Vascular endothelial growth factor-A (VEGF-A) is a potent angiogenesis stimulator known to be involved in pathological angiogenesis in several diseases including colitis. However, the pathogenic importance of specific VEGF-A isoforms during T-cell-mediated experimental colitis remains largely unknown.The CD4⁺ CD45RB(high) T-cell transfer model of experimental colitis was used for these studies. The VEGF lac-Z transgenic reporter mouse was used to examine specific cellular sources of VEGF-A production. The VEGF₁₆₄ aptamer (Macugen), adenoviral VEGF₁₆₄, and the VEGF Trap were used to evaluate pathological importance.VEGF lac-Z reporter mice experiments showed that both infiltrating T cells and local tissue cells produce VEGF-A in the colon during disease. Inhibition of VEGF₁₆₄ using a highly selective RNA aptamer significantly attenuated CD4⁺ CD45RB(high) T-cell-dependent experimental colitis by reducing pathological angiogenesis and inflammatory pathology. Conversely, broad-spectrum VEGF inhibition with VEGF Trap did not attenuate disease, nor did adenoviral VEGF₁₆₄ overexpression significantly alter colitis pathology.VEGF₁₆₄ is actively produced by multiple cell types during T-cell-mediated colitis. Importantly, specific inhibition of the VEGF₁₆₄ isoform during T-cell-mediated colitis dose-dependently attenuated disease progression, while broad-scale inhibition of all VEGF-A isoforms was not therapeutically beneficial. |
| Databáze: | OpenAIRE |
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