Treatment with P28GST, a schistosome-derived enzyme, after acute colitis induction in mice: Decrease of intestinal inflammation associated with a down regulation of Th1/Th17 responses

PLoS One. 2018 Dec 28;13(12):e0209681. doi: 10.1371/journal.pone.0209681. eCollection 2018.

Abstract

Background: P28GST, 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.

Methods: Colitis 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.

Results: Both 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.

Conclusions: These 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers
  • Colitis / drug therapy
  • Colitis / etiology*
  • Colitis / metabolism
  • Colitis / pathology
  • Cytokines / blood
  • Cytokines / metabolism
  • Disease Models, Animal
  • Female
  • Glutathione Transferase / pharmacology*
  • Helminth Proteins / pharmacology*
  • Inflammation Mediators / blood
  • Inflammation Mediators / metabolism
  • Macrophages / immunology
  • Macrophages / metabolism
  • Mice
  • Peroxidase / blood
  • Peroxidase / metabolism
  • Severity of Illness Index
  • Th1 Cells / immunology
  • Th1 Cells / metabolism
  • Th17 Cells / immunology
  • Th17 Cells / metabolism

Substances

  • Biomarkers
  • Cytokines
  • Helminth Proteins
  • Inflammation Mediators
  • Peroxidase
  • Glutathione Transferase

Grant support

This study was supported by the Institut National de la Santé et de la Recherche Médicale (Inserm) and Lille University, as main sponsors of the LIRIC (Lille Inflammation Research International Center). It was also supported by the French National Research Agency (ANR) via the grant ACROHNEM (ANR-11-RPIB-0021), as well as by SATT-NORD (Société d’Accélération du Transfert de Technologies). The funders had no role in study design, data collection and analysis or preparation of the manuscript. Additionally, we acknowledge the supports of the DigestScience Foundation and the FHU IMMINeNT. Digest Science Foundation is a non-profit Foundation recognized as a public interest organization, in order to favor exchanges in the field of Intestinal Bowel Diseases, in the interest of patients: there was no financial support nor material but fruitful exchanges with the research team. The participation as co-author of Dr Christel Rousseaux, member of Intestinal Biotech Development, a small private company, is linked to the funding of the present research project by the (French) National Agency of Research (ANR), in the context of a Call for proposals (ANR RPIB) specifically devoted to reinforce partnerships between Academic teams and Small and Medium Enterprises. The reference of this funding was clearly given in the “financial disclosure of our manuscript“ (ANR-11-RPIB-0021). Both the Academic teams and the IBD Biotech Society received funds from ANR for this specific project. There was absolutely no financial support (salaries or materials) from IBD Biotech to the academic teams. FHU IMMINeNT means Hospital University Federative Project (FHU) of Lille devoted to Immune-mediated inflammatory diseases and targeted therapies. This academic organization will provide support for the publication fee of the present paper.