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PLoS One. 2014 Aug 15;9(8):e103992. doi: 10.1371/journal.pone.0103992. eCollection 2014.

Sequestering HMGB1 via DNA-conjugated beads ameliorates murine colitis.

Author information

1
Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
2
MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
3
SetPoint Medical Corporation, Valencia, California, United States of America.
4
Circulatory Technology Inc., Oyster Bay, New York, United States of America.
5
Medicinal Chemistry, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.

Abstract

Inflammatory bowel disease (IBD) is chronic inflammation of the gastrointestinal tract that affects millions of people worldwide. Although the etiology of IBD is not clear, it is known that products from stressed cells and enteric microbes promote intestinal inflammation. High mobility group box 1 (HMGB1), originally identified as a nuclear DNA binding protein, is a cytokine-like protein mediator implicated in infection, sterile injury, autoimmune disease, and IBD. Elevated levels of HMGB1 have been detected in inflamed human intestinal tissues and in feces of IBD patients and mouse models of colitis. Neutralizing HMGB1 activity by administration of anti-HMGB1 antibodies or HMGB1-specific antagonist improves clinical outcomes in animal models of colitis. Since HMGB1 binds to DNA with high affinity, here we developed a novel strategy to sequester HMGB1 using DNA immobilized on sepharose beads. Screening of DNA-bead constructs revealed that B2 beads, one linear form of DNA conjugated beads, bind HMGB1 with high affinity, capture HMGB1 ex vivo from endotoxin-stimulated RAW 264.7 cell supernatant and from feces of mice with colitis. Oral administration of B2 DNA beads significantly improved body weight, reduced colon injury, and suppressed colonic and circulating cytokine levels in mice with spontaneous colitis (IL-10 knockout) and with dextran sulfate sodium-induced colitis. Thus, DNA beads reduce inflammation by sequestering HMGB1 and may have therapeutic potential for the treatment of IBD.

PMID:
25127031
PMCID:
PMC4134190
DOI:
10.1371/journal.pone.0103992
[Indexed for MEDLINE]
Free PMC Article

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