Basic Study
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. May 28, 2015; 21(20): 6157-6166
Published online May 28, 2015. doi: 10.3748/wjg.v21.i20.6157
Thrombospondin peptide ABT-898 inhibits inflammation and angiogenesis in a colitis model
Linda S Gutierrez, Jun Ling, Derek Nye, Konstantina Papathomas, Catherine Dickinson
Linda S Gutierrez, Derek Nye, Konstantina Papathomas, Catherine Dickinson, Department of Biology and Health Sciences, Wilkes University, Wilkes-Barre, PA 18766, United States
Jun Ling, Department of Basic Sciences, The Commonwealth Medical College, Scranton, PA 18501, United States
Author contributions: Gutierrez LS designed the study, performed some experiments, wrote the manuscript and provided financial support for this work; Ling J performed some experiments, edited the manuscript and provided financial support for this work; Nye D, Papathomas K and Dickinson C performed most of the experiments.
Supported by National Institutes of Health (AREA), No. R15 DK067901-02; the Howard Hughes Medical Institute, No. 52006328; Wilkes Mentoring funds and institutional funds from Wilkes University and TCMC.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Linda S Gutierrez, MD, Department of Biology and Health Sciences, Wilkes University, 230 Cohen Science Center, 84 West South Street, Wilkes-Barre, PA 18766, United States. linda.gutierrez@wilkes.edu
Telephone: +1-570-4084636 Fax: +1-570-4087862
Received: July 25, 2014
Peer-review started: July 26, 2014
First decision: September 27, 2014
Revised: November 10, 2014
Accepted: December 20, 2014
Article in press: December 22, 2014
Published online: May 28, 2015
Abstract

AIM: To evaluate the efficacy of the improved thrombospondin mimetic peptide ABT-898 in a murine model of ulcerative colitis.

METHODS: The dextran sodium sulfate (DSS) was used for the induction of colitis in both TSP-1 deficient (TSP-1-/-) and wild type (WT) mice during 7 d. While mice were receiving the DSS dissolved in the drinking water, the ABT-898 peptide was dissolved in sterile 5% glucose solution and delivered using mini pumps subcutaneously implanted. Plasma samples were analyzed for interleukin (IL)-6 by ELISA assay and colonic tissues were harvested, fixed and processed for histological evaluation. Immunohistochemistry using antibodies for the detection of CD31 and MECA in endothelial cells was performed. Inflammation was graded in colonic sections and the number of microvessels in each lesion was assessed. Activation of signal transducer and activator of transcription 3 (STAT3) in colonic samples was quantified by immunohistochemistry and Western blotting using antibodies against total STAT3 and phosphorylated STAT3 (pSTAT3) (Ser727).

RESULTS: Treatment with ABT-898 considerably diminished the inflammatory response in WT and TSP-1-/- mice (P < 0.0001 in both groups vs control). Identification of blood vessels highlighted by CD31/MECA immunohistochemistry, showed significantly reduced vessel counts in colitic lesions of WT and TSP-1-/- mice treated with ABT898 (TSP-1-/- controls/TSP-1-/- treated, P = 0.0002; WT controls/WT treated, P = 0.0005). Consistently, IL-6 was significantly diminished in plasma samples of TSP-1-/- and WT treated with the peptide when compared to the control mice (P = 0.0002 and P = 0.0148, respectively). pSTAT3 positive cells were quantified in WT and TSP-1-/- treated with ABT-898. A significant decrease in positive cells for pSTAT3 was observed in treated mice (TSP-1-/- controls/TSP-1-/- treated, P = 0.0089; WT/WT treated, P = 0.0110). These results were confirmed by Western blotting analyses showing lower levels of pSTAT3 in colitic lesions from mice treated with the peptide ABT-898.

CONCLUSION: These findings indicate that the new peptide ABT-898 ameliorates inflammation and angiogenesis and might be a therapeutic alternative in IBD and inflammatory diseases.

Keywords: Thrombospondin 1, ABT-898, ABT-510, Angiogenesis, Inflammatory bowel disease, Dextran sodium sulfate model, Interleukin-6, STAT-3

Core tip: Inflammatory bowel disease is still incurable and a major burden in the patient’s life and health care system. The discovery of new and safe therapeutic alternatives is urgently needed. This study tested the efficacy of a new thrombospondin- derived peptide, ABT-898 in a murine model of colitis. Our results indicate that this peptide was able to ameliorate inflammation and angiogenesis. In addition, mice treated with ABT-898 showed significant decrease of plasmatic Interleukin-6 and lesser activation of signal transducer and activator of transcription 3 in colitic lesions. These findings suggest that ABT-898 may indeed be an alternative treatment for inflammatory bowel disease.