Peili Chen1, Danika Bakke1, Lauren Kolodziej1, James Lodolce1, Christopher R Weber2, David L Boone3, F Gary Toback4. 1. Department of Medicine, University of Chicago, Chicago, Illinois. 2. Department of Pathology, University of Chicago, Chicago, Illinois. 3. Department of Medicine, Indiana University School of Medicine, South Bend, Indiana. 4. The University of Chicago, Department of Medicine, MC5100, 5841 South Maryland, Avenue, Chicago, IL.
Abstract
BACKGROUND: A peptide derived from Antrum Mucosal Protein (AMP)-18 (gastrokine-1) reduces the extent of mucosal erosions and clinical severity in mice with dextran sulfate sodium-induced colonic injury. This study set out to determine if AMP peptide was also therapeutic for immune- and cytokine-mediated mouse models of intestinal injury and inflammatory bowel diseases by enhancing and stabilizing tight junctions. METHODS: Therapeutic effects of AMP peptide were examined in interleukin-10-deficient and a T-cell adoptive transfer models of colitis in immunodeficient recombinase activating gene-1 knock-out (RAG-1-/-) mice. Mechanisms by which AMP peptide enhances barrier function and structure were studied ex vivo using intestine and colon from mice given lipopolysaccharide and in AMP-18-deficient mice given dextran sulfate sodium. RESULTS: In interleukin-10-deficient mice given piroxicam, AMP peptide enhanced recovery after weight loss, protected against colon shortening and segmental dilation, and reduced the colitis activity score. In the T-cell transfer model, treatment with the peptide protected against colon shortening. In mice given lipopolysaccharide in vivo to induce gut injury, AMP peptide prevented the onset of, and reversed established intestinal hyperpermeability by targeting TJ proteins and perijunctional actin. AMP-18-deficient mice challenged with dextran sulfate sodium exhibited increased mortality, developed erosions in the colon, and had lower levels of ZO-1 in TJs than heterozygous littermates or wild-type mice. CONCLUSIONS: The results indicate that AMP-18/peptide may serve a protective role against injury along the gastrointestinal mucosal barrier, and recommend further development of AMP peptide as a novel agent to treat patients with inflammatory bowel disease.
BACKGROUND: A peptide derived from Antrum Mucosal Protein (AMP)-18 (gastrokine-1) reduces the extent of mucosal erosions and clinical severity in mice with dextran sulfate sodium-induced colonic injury. This study set out to determine if AMP peptide was also therapeutic for immune- and cytokine-mediated mouse models of intestinal injury and inflammatory bowel diseases by enhancing and stabilizing tight junctions. METHODS: Therapeutic effects of AMP peptide were examined in interleukin-10-deficient and a T-cell adoptive transfer models of colitis in immunodeficient recombinase activating gene-1 knock-out (RAG-1-/-) mice. Mechanisms by which AMP peptide enhances barrier function and structure were studied ex vivo using intestine and colon from mice given lipopolysaccharide and in AMP-18-deficient mice given dextran sulfate sodium. RESULTS: In interleukin-10-deficient mice given piroxicam, AMP peptide enhanced recovery after weight loss, protected against colon shortening and segmental dilation, and reduced the colitis activity score. In the T-cell transfer model, treatment with the peptide protected against colon shortening. In mice given lipopolysaccharide in vivo to induce gut injury, AMP peptide prevented the onset of, and reversed established intestinal hyperpermeability by targeting TJ proteins and perijunctional actin. AMP-18-deficient mice challenged with dextran sulfate sodium exhibited increased mortality, developed erosions in the colon, and had lower levels of ZO-1 in TJs than heterozygous littermates or wild-type mice. CONCLUSIONS: The results indicate that AMP-18/peptide may serve a protective role against injury along the gastrointestinal mucosal barrier, and recommend further development of AMP peptide as a novel agent to treat patients with inflammatory bowel disease.
Authors: Daniel J Berg; Juan Zhang; Joel V Weinstock; Hanan F Ismail; Keith A Earle; Hector Alila; Rifat Pamukcu; Steven Moore; Richard G Lynch Journal: Gastroenterology Date: 2002-11 Impact factor: 22.682
Authors: F Gary Toback; Margaret M Walsh-Reitz; Mark W Musch; Eugene B Chang; John Del Valle; Hongyu Ren; Erick Huang; Terence E Martin Journal: Am J Physiol Gastrointest Liver Physiol Date: 2003-08 Impact factor: 4.052
Authors: K M McCarthy; I B Skare; M C Stankewich; M Furuse; S Tsukita; R A Rogers; R D Lynch; E E Schneeberger Journal: J Cell Sci Date: 1996-09 Impact factor: 5.285
Authors: Hilda Vargas-Robles; Karla Fabiola Castro-Ochoa; Alí Francisco Citalán-Madrid; Michael Schnoor Journal: World J Gastroenterol Date: 2019-08-14 Impact factor: 5.742
Authors: Peili Chen; Maria Mancini; Stephen T Sonis; Juan Fernandez-Martinez; Jing Liu; Ezra E W Cohen; F Gary Toback Journal: PLoS One Date: 2016-04-06 Impact factor: 3.240