Pegylated Arginine Deiminase Downregulates Colitis in Murine Models

Helieh S Oz,Jian Zhong,Willem J S De Villiers

doi:10.1155/2012/813892

Abstract

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. Conclusion. 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.

Highlights

Arginine deiminase (ADI) plays important role in cell signaling pathways, including apoptosis, differentiation, and transcriptional regulation [1, 2]
ADI-polyethylene glycol (PEG) treatment significantly protected dextran sodium sulfate (DSS)-exposed mice from weight loss and rectal bleeding compared to untreated DSS colitic animals
Marked increases in the production of TNFα (Figure 2), IL-6, and IL-12p40 were noted in the stimulated colonic explants (Tables 1 and 2) corresponding to inflammatory response in colitic mice both Interleukin 10 (IL-10) deficient and wildtype mice (WT)

Summary

Introduction

Arginine deiminase (ADI) plays important role in cell signaling pathways, including apoptosis, differentiation, and transcriptional regulation [1, 2]. ADI activity is dysregulated in multiple human diseases including rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and cancer. Nitric oxide (NO) is known to be elevated in the colonic tissues of patients with active IBD and increased NO production and nitric oxide synthase (NOS) activity are detected in cultured mucosal explants from patients with active IBD, both ulcerative colitis and Crohn’s disease [6–9]. Immunohistochemical analysis has identified inducible nitric oxide synthase (iNOS), a key inflammatory mediator, responsible for generation of NO and as the NOS isoform elevated in IBD [10, 11]. This increase-associated iNOS is localized to macrophages and epithelial cells, in luminal epithelia that expose colonic tissue [11]

Methods

Results

Discussion

Conclusion