Pegylated arginine deiminase downregulates colitis in murine models.
Arginine deiminase (ADI), an arginine-metabolizing enzyme involved in cell signaling, is dysregulated in multiple inflammatory diseases and cancers. We hypothesized that pegylated ADI (ADI-PEG) provide protection against colitis.


METHODS
Dextran sodium sulfate colitis was induced in IL-10-deficient and BALB/c (WT) mice. ADI-PEG was administered i.p., and inflammatory mediators and pathology were evaluated.


RESULTS
Acute colitis in mice was manifested by increases in inflammatory biomarkers, such as serum amyloid A (SAA, P < 0.001), IL-12 p40, and disease index (3-Fold). In contrast, ADI-PEG significantly decreased clinical disease index, SAA levels, and inflammatory cytokines in blood as well as in colonic explants. Animals developed moderate (2.2 ± 0.3 WT) to severe (3.6 ± 0.5 IL-10 deficient) colonic pathology; and ADI-PEG treatment significantly improved the severity of colitis (P < 0.05). Marked infiltration of CD68+ macrophages and iNOS expression were detected in colonic submucosa in colitic animals but not detected in ADI-PEG-treated animals.


CONCLUSIONS
ADI-PEG attenuated inflammatory responses by suppression of macrophage infiltration and iNOS expression in colitic animals. ADI-PEG can serve as a potential therapeutic value in IBD.
Department of Physiology, College of Medicine, University of Kentucky Medical Center, Lexington, KY 40515-0298, USA.
Helieh S
HS
Oz
Jian
J
Zhong
Willem J S
WJ
de Villiers
D000818:Animals; D015415:Biomarkers / Q000097:blood; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016264:Dextran Sulfate / Q000494:pharmacology; D004195:Disease Models, Animal; D006801:Humans; D006867:Hydrolases / Q000627:therapeutic use*; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D011092:Polyethylene Glycols / Q000627:therapeutic use*
D015415:Biomarkers; D016753:Interleukin-10; D009569:Nitric Oxide; D011092:Polyethylene Glycols; D016264:Dextran Sulfate; D052247:Nitric Oxide Synthase Type II; D006867:Hydrolases; C512527:ADI PEG20