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Inhibition of DPP4 activity in humans establishes its in vivo role in CXCL10 post‐translational modification: prospective placebo‐controlled clinical studies
Biochemical experiments, animal models, and observational studies in humans all support a role of dipeptidyl peptidase 4 (DPP4) in the N‐terminal truncation of CXCL10, which results in the generation of an antagonist form of the chemokine that limits T‐cell and NK cell migration. Motivated by the ab...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4888857/ https://www.ncbi.nlm.nih.gov/pubmed/27137491 http://dx.doi.org/10.15252/emmm.201506145 |
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author | Decalf, Jérémie Tarbell, Kristin V Casrouge, Armanda Price, Jeffrey D Linder, Grace Mottez, Estelle Sultanik, Philippe Mallet, Vincent Pol, Stanislas Duffy, Darragh Albert, Matthew L |
author_facet | Decalf, Jérémie Tarbell, Kristin V Casrouge, Armanda Price, Jeffrey D Linder, Grace Mottez, Estelle Sultanik, Philippe Mallet, Vincent Pol, Stanislas Duffy, Darragh Albert, Matthew L |
author_sort | Decalf, Jérémie |
collection | PubMed |
description | Biochemical experiments, animal models, and observational studies in humans all support a role of dipeptidyl peptidase 4 (DPP4) in the N‐terminal truncation of CXCL10, which results in the generation of an antagonist form of the chemokine that limits T‐cell and NK cell migration. Motivated by the ability to regulate lymphocyte trafficking in vivo, we conducted two prospective clinical trials to test the effects of DPP4 inhibition on CXCL10 processing in healthy donors and in chronic hepatitis C patients, a disease in which DPP4 levels are found to be elevated. Participants were treated daily with 100 mg sitagliptin, a clinically approved DPP4 inhibitor. Plasma samples were analyzed using an ultrasensitive single‐molecule assay (Simoa) to distinguish the full‐length CXCL10(1–77) from the NH (2)‐truncated CXCL10(3–77), as compared to the total CXCL10 levels. Sitagliptin treatment resulted in a significant decrease in CXCL10(3–77) concentration, a reciprocal increase in CXCL10(1–77), with only minimal effects on total levels of the chemokine. These data provide the first direct evidence that in vivo DPP4 inhibition in humans can preserve the bioactive form of CXCL10, offering new therapeutic opportunities for DPP4 inhibitors. |
format | Online Article Text |
id | pubmed-4888857 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-48888572016-11-28 Inhibition of DPP4 activity in humans establishes its in vivo role in CXCL10 post‐translational modification: prospective placebo‐controlled clinical studies Decalf, Jérémie Tarbell, Kristin V Casrouge, Armanda Price, Jeffrey D Linder, Grace Mottez, Estelle Sultanik, Philippe Mallet, Vincent Pol, Stanislas Duffy, Darragh Albert, Matthew L EMBO Mol Med Reports Biochemical experiments, animal models, and observational studies in humans all support a role of dipeptidyl peptidase 4 (DPP4) in the N‐terminal truncation of CXCL10, which results in the generation of an antagonist form of the chemokine that limits T‐cell and NK cell migration. Motivated by the ability to regulate lymphocyte trafficking in vivo, we conducted two prospective clinical trials to test the effects of DPP4 inhibition on CXCL10 processing in healthy donors and in chronic hepatitis C patients, a disease in which DPP4 levels are found to be elevated. Participants were treated daily with 100 mg sitagliptin, a clinically approved DPP4 inhibitor. Plasma samples were analyzed using an ultrasensitive single‐molecule assay (Simoa) to distinguish the full‐length CXCL10(1–77) from the NH (2)‐truncated CXCL10(3–77), as compared to the total CXCL10 levels. Sitagliptin treatment resulted in a significant decrease in CXCL10(3–77) concentration, a reciprocal increase in CXCL10(1–77), with only minimal effects on total levels of the chemokine. These data provide the first direct evidence that in vivo DPP4 inhibition in humans can preserve the bioactive form of CXCL10, offering new therapeutic opportunities for DPP4 inhibitors. John Wiley and Sons Inc. 2016-04-14 2016-06 /pmc/articles/PMC4888857/ /pubmed/27137491 http://dx.doi.org/10.15252/emmm.201506145 Text en © 2016 The Authors. Published under the terms of the CC BY 4.0 license This is an open access article under the terms of the Creative Commons Attribution 4.0 (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Reports Decalf, Jérémie Tarbell, Kristin V Casrouge, Armanda Price, Jeffrey D Linder, Grace Mottez, Estelle Sultanik, Philippe Mallet, Vincent Pol, Stanislas Duffy, Darragh Albert, Matthew L Inhibition of DPP4 activity in humans establishes its in vivo role in CXCL10 post‐translational modification: prospective placebo‐controlled clinical studies |
title | Inhibition of DPP4 activity in humans establishes its in vivo role in CXCL10 post‐translational modification: prospective placebo‐controlled clinical studies |
title_full | Inhibition of DPP4 activity in humans establishes its in vivo role in CXCL10 post‐translational modification: prospective placebo‐controlled clinical studies |
title_fullStr | Inhibition of DPP4 activity in humans establishes its in vivo role in CXCL10 post‐translational modification: prospective placebo‐controlled clinical studies |
title_full_unstemmed | Inhibition of DPP4 activity in humans establishes its in vivo role in CXCL10 post‐translational modification: prospective placebo‐controlled clinical studies |
title_short | Inhibition of DPP4 activity in humans establishes its in vivo role in CXCL10 post‐translational modification: prospective placebo‐controlled clinical studies |
title_sort | inhibition of dpp4 activity in humans establishes its in vivo role in cxcl10 post‐translational modification: prospective placebo‐controlled clinical studies |
topic | Reports |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4888857/ https://www.ncbi.nlm.nih.gov/pubmed/27137491 http://dx.doi.org/10.15252/emmm.201506145 |
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