Abstract
BackgroundP28GST, a 28Kd glutathione S-transferase enzymatic protein derived from a schistosome helminth prevents experimental colitis when administered subcutaneously in the presence of adjuvant by decreasing pro-inflammatory Th1/Th17 response. Given the antioxidant properties of P28GST, we evaluated its anti-inflammatory potential when administered locally after colitis induction in the absence of adjuvant.MethodsColitis was induced in BALB/c mice by rectal administration of TNBS, followed by two intraperitoneal injections of P28GST at day 1 and day 2. Mice were sacrificed 48h after TNBS administration and evaluated for macroscopic and histological scores, myeloperoxidase (MPO) quantification and cytokine messenger RNA expression in the colonic tissues.ResultsBoth clinical and histological scores significantly decreased in mice treated with P28GST at 5 or 50μg/kg when compared to vehicle- treated mice. A significant reduction of MPO was detected in colonic tissues from P28GST–treated mice, similarly to mice treated with methylprednisolone as the reference treatment. Pro-inflammatory cytokines TNF, IL-1β, and IL-6, mRNA as well as serum levels were down-regulated in mice colonic tissues treated with P28GST at 5 or 50μg/kg. In addition, a significant decrease of mRNA expression levels of T-bet, and ROR-γ, respective markers of Th1 and Th17 cells was observed. Whereas no significant effect was detected on Gata3 mRNA, a marker of Th2 cells, the Arg/iNOS mRNA levels significantly increased in P28GST-treated mice, suggesting the induction of M2 macrophages.ConclusionsThese findings provide evidence that P28GST injected locally after colitis induction induces a potent decrease of colitis inflammation in mice, associated to downregulation of Th1/Th17 response, and induction of anti-inflammatory alternatively activated macrophages.
Highlights
Inflammatory Bowel Diseases (IBD) are immune-mediated inflammatory disorders of the digestive tract including Crohn’s disease (CD) and ulcerative colitis (UC)
A significant reduction of MPO was detected in colonic tissues from P28GST–treated mice, to mice treated with methylprednisolone as the reference treatment
Pro-inflammatory cytokines Tumor Necrosis Factor (TNF), IL-1β, and IL6, mRNA as well as serum levels were down-regulated in mice colonic tissues treated with P28GST at 5 or 50μg/kg
Summary
Inflammatory Bowel Diseases (IBD) are immune-mediated inflammatory disorders of the digestive tract including Crohn’s disease (CD) and ulcerative colitis (UC). CD is associated with a T helper type 1 (Th1)/Th17 response, with pro-inflammatory Th1 cells expressing large amounts of pro-inflammatory cytokines such as Interferon-γ (IFN-γ), Tumor Necrosis Factor (TNF) and Interleukin-1β (IL-1β) in the intestinal mucosa. Th17 cells massively infiltrate the inflamed intestine of patients where they produce IL-17 that mediates pro-inflammatory functions including upregulation of TNF and IL-1β, recruitment of neutrophils and secretion of matrix metalloproteinases by intestinal fibroblasts [1]. Controlling the expression and the activity of pro-inflammatory cytokines is an approach that needs to combine anti-inflammatory efficacy with low suppressive effects on immune defense. Given the antioxidant properties of P28GST, we evaluated its anti-inflammatory potential when administered locally after colitis induction in the absence of adjuvant
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