Functional Modulation of Crohn’s Disease Myofibroblasts by Anti-Tumor Necrosis Factor Antibodies

Autores
Di Sabatino, Antonio; Pender, Sylvia L.F.; Jackson, Claire L.; Prothero, Joanna D.; Gordon, John N.; Picariello, Lucia; Rovedatti, Laura; Docena, Guillermo H.; Monteleone, Giovanni; Rampton, David S.; Tonelli, Francesco; Corazza, Gino R.; MacDonald, Thomas T.
Año de publicación
2007
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Infliximab induces immune cell apoptosis by outside-to-inside signaling through transmembrane tumor necrosis factor-α (mTNF). However, in inflamed gut, myofibroblasts also produce TNF-α, and the affects of anti-TNF antibodies on these structural cells are unknown. We investigated the action of infliximab on apoptosis, the production of matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMP)-1, and migration of Crohn’s disease (CD) myofibroblasts. Methods: Colonic myofibroblasts were isolated from patients with active CD and controls. mTNF was evaluated by Western blotting and flow cytometry. Infliximab-treated myofibroblasts were analyzed for apoptosis by Annexin V staining and caspase-3. TIMP-1 and MMPs were measured by Western blotting, and fibroblast migration was assessed by using an in vitro wound-healing scratch assay. Results: CD myofibroblasts showed higher mTNF expression than control myofibroblasts. Infliximab had no effect on CD myofibroblast apoptosis, caspase-3 activation, and production of MMP-3 and MMP-12. However, infliximab induced a significant dose-dependent increase in TIMP-1 production, which was inhibited by the p38 mitogen-activated protein kinase inhibitor SB 203580. The anti-TNF agents adalimumab, etanercept, and p55 TNF-receptor–human IgG fusion protein also increased TIMP-1 production. The migration of CD myofibroblasts was enhanced significantly by infliximab and recombinant human TIMP-1, and infliximab-induced migration was inhibited by anti–TIMP-1 neutralizing antibody. Infliximab also decreased CD myofibroblast collagen production. Conclusions: Our findings show a novel therapeutic pathway for anti-TNF therapies in enhancing TIMP-1 production and myofibroblast migration, which may reduce MMP activity and facilitate the wound healing.
Fil: Di Sabatino, Antonio. Universita Degli Studi Di Pavia; Italia
Fil: Pender, Sylvia L.F.. University of Southampton; Reino Unido
Fil: Jackson, Claire L.. University of Southampton; Reino Unido
Fil: Prothero, Joanna D.. University of Southampton; Reino Unido
Fil: Gordon, John N.. Royal Hampshire County Hospital; Reino Unido
Fil: Picariello, Lucia. Università degli Studi di Firenze; Italia
Fil: Rovedatti, Laura. Universita Degli Studi Di Pavia; Italia
Fil: Docena, Guillermo H.. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Centro de Investigación y Desarrollo en Criotecnología de Alimentos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigación y Desarrollo en Criotecnología de Alimentos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Centro de Investigación y Desarrollo en Criotecnología de Alimentos; Argentina
Fil: Monteleone, Giovanni. Universita Tor Vergata; Italia
Fil: Rampton, David S.. The Royal London Hospital; Reino Unido
Fil: Tonelli, Francesco. Università degli Studi di Firenze; Italia
Fil: Corazza, Gino R.. Universita Degli Studi Di Pavia; Italia
Fil: MacDonald, Thomas T.. Barts and The London School of Medicine and Dentistry; Reino Unido
Materia
IBD
TNF
INFLIXIMAB
MYOFIBROBLAST
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/111027
Acceder
id CONICETDig_9c388c49898186f1f948f6abbfeff698
oai_identifier_str oai:ri.conicet.gov.ar:11336/111027
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Functional Modulation of Crohn’s Disease Myofibroblasts by Anti-Tumor Necrosis Factor AntibodiesDi Sabatino, AntonioPender, Sylvia L.F.Jackson, Claire L.Prothero, Joanna D.Gordon, John N.Picariello, LuciaRovedatti, LauraDocena, Guillermo H.Monteleone, GiovanniRampton, David S.Tonelli, FrancescoCorazza, Gino R.MacDonald, Thomas T.IBDTNFINFLIXIMABMYOFIBROBLASThttps://purl.org/becyt/ford/3.3https://purl.org/becyt/ford/3Infliximab induces immune cell apoptosis by outside-to-inside signaling through transmembrane tumor necrosis factor-α (mTNF). However, in inflamed gut, myofibroblasts also produce TNF-α, and the affects of anti-TNF antibodies on these structural cells are unknown. We investigated the action of infliximab on apoptosis, the production of matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMP)-1, and migration of Crohn’s disease (CD) myofibroblasts. Methods: Colonic myofibroblasts were isolated from patients with active CD and controls. mTNF was evaluated by Western blotting and flow cytometry. Infliximab-treated myofibroblasts were analyzed for apoptosis by Annexin V staining and caspase-3. TIMP-1 and MMPs were measured by Western blotting, and fibroblast migration was assessed by using an in vitro wound-healing scratch assay. Results: CD myofibroblasts showed higher mTNF expression than control myofibroblasts. Infliximab had no effect on CD myofibroblast apoptosis, caspase-3 activation, and production of MMP-3 and MMP-12. However, infliximab induced a significant dose-dependent increase in TIMP-1 production, which was inhibited by the p38 mitogen-activated protein kinase inhibitor SB 203580. The anti-TNF agents adalimumab, etanercept, and p55 TNF-receptor–human IgG fusion protein also increased TIMP-1 production. The migration of CD myofibroblasts was enhanced significantly by infliximab and recombinant human TIMP-1, and infliximab-induced migration was inhibited by anti–TIMP-1 neutralizing antibody. Infliximab also decreased CD myofibroblast collagen production. Conclusions: Our findings show a novel therapeutic pathway for anti-TNF therapies in enhancing TIMP-1 production and myofibroblast migration, which may reduce MMP activity and facilitate the wound healing.Fil: Di Sabatino, Antonio. Universita Degli Studi Di Pavia; ItaliaFil: Pender, Sylvia L.F.. University of Southampton; Reino UnidoFil: Jackson, Claire L.. University of Southampton; Reino UnidoFil: Prothero, Joanna D.. University of Southampton; Reino UnidoFil: Gordon, John N.. Royal Hampshire County Hospital; Reino UnidoFil: Picariello, Lucia. Università degli Studi di Firenze; ItaliaFil: Rovedatti, Laura. Universita Degli Studi Di Pavia; ItaliaFil: Docena, Guillermo H.. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Centro de Investigación y Desarrollo en Criotecnología de Alimentos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigación y Desarrollo en Criotecnología de Alimentos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Centro de Investigación y Desarrollo en Criotecnología de Alimentos; ArgentinaFil: Monteleone, Giovanni. Universita Tor Vergata; ItaliaFil: Rampton, David S.. The Royal London Hospital; Reino UnidoFil: Tonelli, Francesco. Università degli Studi di Firenze; ItaliaFil: Corazza, Gino R.. Universita Degli Studi Di Pavia; ItaliaFil: MacDonald, Thomas T.. Barts and The London School of Medicine and Dentistry; Reino UnidoW B Saunders Co-Elsevier Inc2007-07info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/111027Di Sabatino, Antonio; Pender, Sylvia L.F.; Jackson, Claire L.; Prothero, Joanna D.; Gordon, John N.; et al.; Functional Modulation of Crohn’s Disease Myofibroblasts by Anti-Tumor Necrosis Factor Antibodies; W B Saunders Co-Elsevier Inc; Gastroenterology; 133; 1; 7-2007; 137-1490016-50851528-0012CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/abs/pii/S0016508507009262info:eu-repo/semantics/altIdentifier/doi/10.1053/j.gastro.2007.04.069info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T11:47:24Zoai:ri.conicet.gov.ar:11336/111027instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-22 11:47:24.834CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Functional Modulation of Crohn’s Disease Myofibroblasts by Anti-Tumor Necrosis Factor Antibodies
title Functional Modulation of Crohn’s Disease Myofibroblasts by Anti-Tumor Necrosis Factor Antibodies
spellingShingle Functional Modulation of Crohn’s Disease Myofibroblasts by Anti-Tumor Necrosis Factor Antibodies
Di Sabatino, Antonio
IBD
TNF
INFLIXIMAB
MYOFIBROBLAST
title_short Functional Modulation of Crohn’s Disease Myofibroblasts by Anti-Tumor Necrosis Factor Antibodies
title_full Functional Modulation of Crohn’s Disease Myofibroblasts by Anti-Tumor Necrosis Factor Antibodies
title_fullStr Functional Modulation of Crohn’s Disease Myofibroblasts by Anti-Tumor Necrosis Factor Antibodies
title_full_unstemmed Functional Modulation of Crohn’s Disease Myofibroblasts by Anti-Tumor Necrosis Factor Antibodies
title_sort Functional Modulation of Crohn’s Disease Myofibroblasts by Anti-Tumor Necrosis Factor Antibodies
dc.creator.none.fl_str_mv Di Sabatino, Antonio
Pender, Sylvia L.F.
Jackson, Claire L.
Prothero, Joanna D.
Gordon, John N.
Picariello, Lucia
Rovedatti, Laura
Docena, Guillermo H.
Monteleone, Giovanni
Rampton, David S.
Tonelli, Francesco
Corazza, Gino R.
MacDonald, Thomas T.
author Di Sabatino, Antonio
author_facet Di Sabatino, Antonio
Pender, Sylvia L.F.
Jackson, Claire L.
Prothero, Joanna D.
Gordon, John N.
Picariello, Lucia
Rovedatti, Laura
Docena, Guillermo H.
Monteleone, Giovanni
Rampton, David S.
Tonelli, Francesco
Corazza, Gino R.
MacDonald, Thomas T.
author_role author
author2 Pender, Sylvia L.F.
Jackson, Claire L.
Prothero, Joanna D.
Gordon, John N.
Picariello, Lucia
Rovedatti, Laura
Docena, Guillermo H.
Monteleone, Giovanni
Rampton, David S.
Tonelli, Francesco
Corazza, Gino R.
MacDonald, Thomas T.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv IBD
TNF
INFLIXIMAB
MYOFIBROBLAST
topic IBD
TNF
INFLIXIMAB
MYOFIBROBLAST
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.3
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Infliximab induces immune cell apoptosis by outside-to-inside signaling through transmembrane tumor necrosis factor-α (mTNF). However, in inflamed gut, myofibroblasts also produce TNF-α, and the affects of anti-TNF antibodies on these structural cells are unknown. We investigated the action of infliximab on apoptosis, the production of matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMP)-1, and migration of Crohn’s disease (CD) myofibroblasts. Methods: Colonic myofibroblasts were isolated from patients with active CD and controls. mTNF was evaluated by Western blotting and flow cytometry. Infliximab-treated myofibroblasts were analyzed for apoptosis by Annexin V staining and caspase-3. TIMP-1 and MMPs were measured by Western blotting, and fibroblast migration was assessed by using an in vitro wound-healing scratch assay. Results: CD myofibroblasts showed higher mTNF expression than control myofibroblasts. Infliximab had no effect on CD myofibroblast apoptosis, caspase-3 activation, and production of MMP-3 and MMP-12. However, infliximab induced a significant dose-dependent increase in TIMP-1 production, which was inhibited by the p38 mitogen-activated protein kinase inhibitor SB 203580. The anti-TNF agents adalimumab, etanercept, and p55 TNF-receptor–human IgG fusion protein also increased TIMP-1 production. The migration of CD myofibroblasts was enhanced significantly by infliximab and recombinant human TIMP-1, and infliximab-induced migration was inhibited by anti–TIMP-1 neutralizing antibody. Infliximab also decreased CD myofibroblast collagen production. Conclusions: Our findings show a novel therapeutic pathway for anti-TNF therapies in enhancing TIMP-1 production and myofibroblast migration, which may reduce MMP activity and facilitate the wound healing.
Fil: Di Sabatino, Antonio. Universita Degli Studi Di Pavia; Italia
Fil: Pender, Sylvia L.F.. University of Southampton; Reino Unido
Fil: Jackson, Claire L.. University of Southampton; Reino Unido
Fil: Prothero, Joanna D.. University of Southampton; Reino Unido
Fil: Gordon, John N.. Royal Hampshire County Hospital; Reino Unido
Fil: Picariello, Lucia. Università degli Studi di Firenze; Italia
Fil: Rovedatti, Laura. Universita Degli Studi Di Pavia; Italia
Fil: Docena, Guillermo H.. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Centro de Investigación y Desarrollo en Criotecnología de Alimentos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigación y Desarrollo en Criotecnología de Alimentos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Centro de Investigación y Desarrollo en Criotecnología de Alimentos; Argentina
Fil: Monteleone, Giovanni. Universita Tor Vergata; Italia
Fil: Rampton, David S.. The Royal London Hospital; Reino Unido
Fil: Tonelli, Francesco. Università degli Studi di Firenze; Italia
Fil: Corazza, Gino R.. Universita Degli Studi Di Pavia; Italia
Fil: MacDonald, Thomas T.. Barts and The London School of Medicine and Dentistry; Reino Unido
description Infliximab induces immune cell apoptosis by outside-to-inside signaling through transmembrane tumor necrosis factor-α (mTNF). However, in inflamed gut, myofibroblasts also produce TNF-α, and the affects of anti-TNF antibodies on these structural cells are unknown. We investigated the action of infliximab on apoptosis, the production of matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMP)-1, and migration of Crohn’s disease (CD) myofibroblasts. Methods: Colonic myofibroblasts were isolated from patients with active CD and controls. mTNF was evaluated by Western blotting and flow cytometry. Infliximab-treated myofibroblasts were analyzed for apoptosis by Annexin V staining and caspase-3. TIMP-1 and MMPs were measured by Western blotting, and fibroblast migration was assessed by using an in vitro wound-healing scratch assay. Results: CD myofibroblasts showed higher mTNF expression than control myofibroblasts. Infliximab had no effect on CD myofibroblast apoptosis, caspase-3 activation, and production of MMP-3 and MMP-12. However, infliximab induced a significant dose-dependent increase in TIMP-1 production, which was inhibited by the p38 mitogen-activated protein kinase inhibitor SB 203580. The anti-TNF agents adalimumab, etanercept, and p55 TNF-receptor–human IgG fusion protein also increased TIMP-1 production. The migration of CD myofibroblasts was enhanced significantly by infliximab and recombinant human TIMP-1, and infliximab-induced migration was inhibited by anti–TIMP-1 neutralizing antibody. Infliximab also decreased CD myofibroblast collagen production. Conclusions: Our findings show a novel therapeutic pathway for anti-TNF therapies in enhancing TIMP-1 production and myofibroblast migration, which may reduce MMP activity and facilitate the wound healing.
publishDate 2007
dc.date.none.fl_str_mv 2007-07
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/111027
Di Sabatino, Antonio; Pender, Sylvia L.F.; Jackson, Claire L.; Prothero, Joanna D.; Gordon, John N.; et al.; Functional Modulation of Crohn’s Disease Myofibroblasts by Anti-Tumor Necrosis Factor Antibodies; W B Saunders Co-Elsevier Inc; Gastroenterology; 133; 1; 7-2007; 137-149
0016-5085
1528-0012
CONICET Digital
CONICET
url http://hdl.handle.net/11336/111027
identifier_str_mv Di Sabatino, Antonio; Pender, Sylvia L.F.; Jackson, Claire L.; Prothero, Joanna D.; Gordon, John N.; et al.; Functional Modulation of Crohn’s Disease Myofibroblasts by Anti-Tumor Necrosis Factor Antibodies; W B Saunders Co-Elsevier Inc; Gastroenterology; 133; 1; 7-2007; 137-149
0016-5085
1528-0012
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/abs/pii/S0016508507009262
info:eu-repo/semantics/altIdentifier/doi/10.1053/j.gastro.2007.04.069
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv W B Saunders Co-Elsevier Inc
publisher.none.fl_str_mv W B Saunders Co-Elsevier Inc
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
_version_ 1846782179738124288
score 12.982451

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