Gp96 Peptide Antagonist gp96-II Confers Therapeutic Effects in Murine Intestinal Inflammation

Nold-Petry CA, Nold MF, Levy O, Kliger Y, Oren A, Borukhov I, Becker C, Wirtz S, Sandhu MK, Neurath M, Dinarello CA (2017)

Publication Type: Journal article

Publication year: 2017

Journal

Frontiers in Immunology Frontiers Research Foundation / Frontiers Media

Book Volume: 8

DOI: 10.3389/fimmu.2017.01531

Abstract

Background: The expression of heat shock protein gp96 is strongly correlated with the degree of tissue inflammation in ulcerative colitis and Crohn's disease, thereby leading us to the hypothesis that inhibition of expression via gp96-II peptide prevents intestinal inflammation. Methods: We employed daily injections of gp96-II peptide in two murine models of intestinal inflammation, the first resulting from five daily injections of IL-12/IL-18, the second via a single intrarectal application of TNBS (2,4,6-trinitrobenzenesulfonic acid). We also assessed the effectiveness of gp96-II peptide in murine and human primary cell culture. Results: In the IL-12/IL-18 model, all gp96-II peptide-treated animals survived until day 5, whereas 80% of placebo-injected animals died. gp96-II peptide reduced IL-12/IL-18-induced plasma IFNγ by 89%, IL-1β by 63%, IL-6 by 43% and tumor necrosis factor (TNF) by 70% compared to controls. The clinical assessment Disease Activity Index of intestinal inflammation severity was found to be significantly lower in the gp96-II-treated animals when compared to vehicle-injected mice. gp96-II peptide treatment in the TNBS model limited weight loss to 5% on day 7 compared with prednisolone treatment, whereas placebo-treated animals suffered a 20% weight loss. Histological disease severity was reduced equally by prednisolone (by 40%) and gp96-II peptide (35%). Mice treated with either gp96-II peptide or prednisolone exhibited improved endoscopic scores compared with vehicle-treated control mice: vascularity, fibrin, granularity, and translucency scores were reduced by up to 49% by prednisolone and by up to 30% by gp96-II peptide. In vitro, gp96-II peptide reduced TLR2-, TLR4- and IL-12/IL-18-induced cytokine expression in murine splenocytes, with declines in constitutive IL-6 (54%), lipopolysaccharide-induced TNF (48%), IL-6 (81%) and in Staphylococcus epidermidis-induced TNF (67%) and IL-6 (81%), as well as IL-12/IL-18-induced IFNγ (75%). gp96-II peptide reduced IL-1β, IL-6, TNF and GM-CSF in human peripheral blood mononuclear cells to a similar degree without affecting cell viability, whereas RANTES, IL-25 and MIF were twofold to threefold increased. Conclusion: gp96-II peptide protects against murine intestinal inflammation by regulating inflammation in vivo and in vitro, pointing to its promise as a novel treatment for inflammatory bowel disease.

Authors with CRIS profile

Christoph Becker Professur für Molekulare Gastroenterologie Stefan Wirtz Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Markus Neurath Lehrstuhl für Innere Medizin I

Involved external institutions

Hudson Institute of Medical Research AU Australia (AU) Compugen Ltd. IL Israel (IL) University of Colorado System US United States (USA) (US)

How to cite

APA:

Nold-Petry, C.A., Nold, M.F., Levy, O., Kliger, Y., Oren, A., Borukhov, I.,... Dinarello, C.A. (2017). Gp96 Peptide Antagonist gp96-II Confers Therapeutic Effects in Murine Intestinal Inflammation. Frontiers in Immunology, 8. https://doi.org/10.3389/fimmu.2017.01531

MLA:

Nold-Petry, Claudia A., et al. "Gp96 Peptide Antagonist gp96-II Confers Therapeutic Effects in Murine Intestinal Inflammation." Frontiers in Immunology 8 (2017).

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