Cargando…

Pancreatic β-Cell–Derived IP-10/CXCL10 Isletokine Mediates Early Loss of Graft Function in Islet Cell Transplantation

Pancreatic islets produce and secrete cytokines and chemokines in response to inflammatory and metabolic stress. The physiological role of these “isletokines” in health and disease is largely unknown. We observed that islets release multiple inflammatory mediators in patients undergoing islet transp...

Descripción completa

Detalles Bibliográficos
Autores principales: Yoshimatsu, Gumpei, Kunnathodi, Faisal, Saravanan, Prathab Balaji, Shahbazov, Rauf, Chang, Charles, Darden, Carly M., Zurawski, Sandra, Boyuk, Gulbahar, Kanak, Mazhar A., Levy, Marlon F., Naziruddin, Bashoo, Lawrence, Michael C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5652609/
https://www.ncbi.nlm.nih.gov/pubmed/28855240
http://dx.doi.org/10.2337/db17-0578
_version_ 1783273090103377920
author Yoshimatsu, Gumpei
Kunnathodi, Faisal
Saravanan, Prathab Balaji
Shahbazov, Rauf
Chang, Charles
Darden, Carly M.
Zurawski, Sandra
Boyuk, Gulbahar
Kanak, Mazhar A.
Levy, Marlon F.
Naziruddin, Bashoo
Lawrence, Michael C.
author_facet Yoshimatsu, Gumpei
Kunnathodi, Faisal
Saravanan, Prathab Balaji
Shahbazov, Rauf
Chang, Charles
Darden, Carly M.
Zurawski, Sandra
Boyuk, Gulbahar
Kanak, Mazhar A.
Levy, Marlon F.
Naziruddin, Bashoo
Lawrence, Michael C.
author_sort Yoshimatsu, Gumpei
collection PubMed
description Pancreatic islets produce and secrete cytokines and chemokines in response to inflammatory and metabolic stress. The physiological role of these “isletokines” in health and disease is largely unknown. We observed that islets release multiple inflammatory mediators in patients undergoing islet transplants within hours of infusion. The proinflammatory cytokine interferon-γ–induced protein 10 (IP-10/CXCL10) was among the highest released, and high levels correlated with poor islet transplant outcomes. Transgenic mouse studies confirmed that donor islet–specific expression of IP-10 contributed to islet inflammation and loss of β-cell function in islet grafts. The effects of islet-derived IP-10 could be blocked by treatment of donor islets and recipient mice with anti–IP-10 neutralizing monoclonal antibody. In vitro studies showed induction of the IP-10 gene was mediated by calcineurin-dependent NFAT signaling in pancreatic β-cells in response to oxidative or inflammatory stress. Sustained association of NFAT and p300 histone acetyltransferase with the IP-10 gene required p38 and c-Jun N-terminal kinase mitogen-activated protein kinase (MAPK) activity, which differentially regulated IP-10 expression and subsequent protein release. Overall, these findings elucidate an NFAT-MAPK signaling paradigm for induction of isletokine expression in β-cells and reveal IP-10 as a primary therapeutic target to prevent β-cell–induced inflammatory loss of graft function after islet cell transplantation.
format Online
Article
Text
id pubmed-5652609
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher American Diabetes Association
record_format MEDLINE/PubMed
spelling pubmed-56526092018-11-01 Pancreatic β-Cell–Derived IP-10/CXCL10 Isletokine Mediates Early Loss of Graft Function in Islet Cell Transplantation Yoshimatsu, Gumpei Kunnathodi, Faisal Saravanan, Prathab Balaji Shahbazov, Rauf Chang, Charles Darden, Carly M. Zurawski, Sandra Boyuk, Gulbahar Kanak, Mazhar A. Levy, Marlon F. Naziruddin, Bashoo Lawrence, Michael C. Diabetes Immunology and Transplantation Pancreatic islets produce and secrete cytokines and chemokines in response to inflammatory and metabolic stress. The physiological role of these “isletokines” in health and disease is largely unknown. We observed that islets release multiple inflammatory mediators in patients undergoing islet transplants within hours of infusion. The proinflammatory cytokine interferon-γ–induced protein 10 (IP-10/CXCL10) was among the highest released, and high levels correlated with poor islet transplant outcomes. Transgenic mouse studies confirmed that donor islet–specific expression of IP-10 contributed to islet inflammation and loss of β-cell function in islet grafts. The effects of islet-derived IP-10 could be blocked by treatment of donor islets and recipient mice with anti–IP-10 neutralizing monoclonal antibody. In vitro studies showed induction of the IP-10 gene was mediated by calcineurin-dependent NFAT signaling in pancreatic β-cells in response to oxidative or inflammatory stress. Sustained association of NFAT and p300 histone acetyltransferase with the IP-10 gene required p38 and c-Jun N-terminal kinase mitogen-activated protein kinase (MAPK) activity, which differentially regulated IP-10 expression and subsequent protein release. Overall, these findings elucidate an NFAT-MAPK signaling paradigm for induction of isletokine expression in β-cells and reveal IP-10 as a primary therapeutic target to prevent β-cell–induced inflammatory loss of graft function after islet cell transplantation. American Diabetes Association 2017-11 2017-08-30 /pmc/articles/PMC5652609/ /pubmed/28855240 http://dx.doi.org/10.2337/db17-0578 Text en © 2017 by the American Diabetes Association. http://www.diabetesjournals.org/content/licenseReaders may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.
spellingShingle Immunology and Transplantation
Yoshimatsu, Gumpei
Kunnathodi, Faisal
Saravanan, Prathab Balaji
Shahbazov, Rauf
Chang, Charles
Darden, Carly M.
Zurawski, Sandra
Boyuk, Gulbahar
Kanak, Mazhar A.
Levy, Marlon F.
Naziruddin, Bashoo
Lawrence, Michael C.
Pancreatic β-Cell–Derived IP-10/CXCL10 Isletokine Mediates Early Loss of Graft Function in Islet Cell Transplantation
title Pancreatic β-Cell–Derived IP-10/CXCL10 Isletokine Mediates Early Loss of Graft Function in Islet Cell Transplantation
title_full Pancreatic β-Cell–Derived IP-10/CXCL10 Isletokine Mediates Early Loss of Graft Function in Islet Cell Transplantation
title_fullStr Pancreatic β-Cell–Derived IP-10/CXCL10 Isletokine Mediates Early Loss of Graft Function in Islet Cell Transplantation
title_full_unstemmed Pancreatic β-Cell–Derived IP-10/CXCL10 Isletokine Mediates Early Loss of Graft Function in Islet Cell Transplantation
title_short Pancreatic β-Cell–Derived IP-10/CXCL10 Isletokine Mediates Early Loss of Graft Function in Islet Cell Transplantation
title_sort pancreatic β-cell–derived ip-10/cxcl10 isletokine mediates early loss of graft function in islet cell transplantation
topic Immunology and Transplantation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5652609/
https://www.ncbi.nlm.nih.gov/pubmed/28855240
http://dx.doi.org/10.2337/db17-0578
work_keys_str_mv AT yoshimatsugumpei pancreaticbcellderivedip10cxcl10isletokinemediatesearlylossofgraftfunctioninisletcelltransplantation
AT kunnathodifaisal pancreaticbcellderivedip10cxcl10isletokinemediatesearlylossofgraftfunctioninisletcelltransplantation
AT saravananprathabbalaji pancreaticbcellderivedip10cxcl10isletokinemediatesearlylossofgraftfunctioninisletcelltransplantation
AT shahbazovrauf pancreaticbcellderivedip10cxcl10isletokinemediatesearlylossofgraftfunctioninisletcelltransplantation
AT changcharles pancreaticbcellderivedip10cxcl10isletokinemediatesearlylossofgraftfunctioninisletcelltransplantation
AT dardencarlym pancreaticbcellderivedip10cxcl10isletokinemediatesearlylossofgraftfunctioninisletcelltransplantation
AT zurawskisandra pancreaticbcellderivedip10cxcl10isletokinemediatesearlylossofgraftfunctioninisletcelltransplantation
AT boyukgulbahar pancreaticbcellderivedip10cxcl10isletokinemediatesearlylossofgraftfunctioninisletcelltransplantation
AT kanakmazhara pancreaticbcellderivedip10cxcl10isletokinemediatesearlylossofgraftfunctioninisletcelltransplantation
AT levymarlonf pancreaticbcellderivedip10cxcl10isletokinemediatesearlylossofgraftfunctioninisletcelltransplantation
AT naziruddinbashoo pancreaticbcellderivedip10cxcl10isletokinemediatesearlylossofgraftfunctioninisletcelltransplantation
AT lawrencemichaelc pancreaticbcellderivedip10cxcl10isletokinemediatesearlylossofgraftfunctioninisletcelltransplantation