Cargando…

IL-6–Dependent STAT3 Activation and Induction of Proinflammatory Cytokines in Primary Sclerosing Cholangitis

INTRODUCTION: Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease with periductal inflammation and fibrosis. Genetic studies suggest inflammatory cytokines and IL-6–dependent activation of transcription factor STAT3 as pivotal steps in PSC pathogenesis. However, details of infla...

Descripción completa

Detalles Bibliográficos
Autores principales: Dold, Leona, Frank, Leonie, Lutz, Philipp, Kaczmarek, Dominik J., Krämer, Benjamin, Nattermann, Jacob, Weismüller, Tobias J., Branchi, Vittorio, Toma, Marieta, Gonzalez-Carmona, Maria, Strassburg, Christian P., Spengler, Ulrich, Langhans, Bettina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Wolters Kluwer 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10461951/
https://www.ncbi.nlm.nih.gov/pubmed/37256725
http://dx.doi.org/10.14309/ctg.0000000000000603
_version_ 1785097963038572544
author Dold, Leona
Frank, Leonie
Lutz, Philipp
Kaczmarek, Dominik J.
Krämer, Benjamin
Nattermann, Jacob
Weismüller, Tobias J.
Branchi, Vittorio
Toma, Marieta
Gonzalez-Carmona, Maria
Strassburg, Christian P.
Spengler, Ulrich
Langhans, Bettina
author_facet Dold, Leona
Frank, Leonie
Lutz, Philipp
Kaczmarek, Dominik J.
Krämer, Benjamin
Nattermann, Jacob
Weismüller, Tobias J.
Branchi, Vittorio
Toma, Marieta
Gonzalez-Carmona, Maria
Strassburg, Christian P.
Spengler, Ulrich
Langhans, Bettina
author_sort Dold, Leona
collection PubMed
description INTRODUCTION: Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease with periductal inflammation and fibrosis. Genetic studies suggest inflammatory cytokines and IL-6–dependent activation of transcription factor STAT3 as pivotal steps in PSC pathogenesis. However, details of inflammatory regulation remain unclear. METHODS: We recruited 50 patients with PSC (36 with inflammatory bowel disease, 14 without inflammatory bowel disease), 12 patients with autoimmune hepatitis, and 36 healthy controls to measure cytokines in the serum, bile, and immune cell supernatant using bead-based immunoassays and flow cytometry and immunohistochemistry to analyze phosphorylation of STATs in immune cells. Finally, we analyzed cytokines and STAT3 phosphorylation of T cells in the presence of JAK1/2 inhibitors. RESULTS: In PSC, IL-6 specifically triggered phosphorylation of STAT3 in CD4(+) T cells and lead to enhanced production of interferon (IFN) gamma and interleukin (IL)-17A. Phospho-STAT3–positive CD4(+) T cells correlated with systemic inflammation (C-reactive protein serum levels). Combination of immunohistology and flow cytometry indicated that phospho-STAT3–positive cells were enriched in the peribiliary liver stroma and represented CD4(+) T cells with prominent production of IFN gamma and IL-17A. JAK1/2 inhibitors blocked STAT3 phosphorylation and production of IFN gamma and IL-6, whereas IL-17A was apparently resistant to this inhibition. DISCUSSION: Our results demonstrate systemic and local activation of the IL-6/STAT3 pathway in PSC. Resistance of IL-17A to STAT3-targeted inhibition points to a more complex immune dysregulation beyond STAT3 activation.
format Online
Article
Text
id pubmed-10461951
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher Wolters Kluwer
record_format MEDLINE/PubMed
spelling pubmed-104619512023-08-29 IL-6–Dependent STAT3 Activation and Induction of Proinflammatory Cytokines in Primary Sclerosing Cholangitis Dold, Leona Frank, Leonie Lutz, Philipp Kaczmarek, Dominik J. Krämer, Benjamin Nattermann, Jacob Weismüller, Tobias J. Branchi, Vittorio Toma, Marieta Gonzalez-Carmona, Maria Strassburg, Christian P. Spengler, Ulrich Langhans, Bettina Clin Transl Gastroenterol Article INTRODUCTION: Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease with periductal inflammation and fibrosis. Genetic studies suggest inflammatory cytokines and IL-6–dependent activation of transcription factor STAT3 as pivotal steps in PSC pathogenesis. However, details of inflammatory regulation remain unclear. METHODS: We recruited 50 patients with PSC (36 with inflammatory bowel disease, 14 without inflammatory bowel disease), 12 patients with autoimmune hepatitis, and 36 healthy controls to measure cytokines in the serum, bile, and immune cell supernatant using bead-based immunoassays and flow cytometry and immunohistochemistry to analyze phosphorylation of STATs in immune cells. Finally, we analyzed cytokines and STAT3 phosphorylation of T cells in the presence of JAK1/2 inhibitors. RESULTS: In PSC, IL-6 specifically triggered phosphorylation of STAT3 in CD4(+) T cells and lead to enhanced production of interferon (IFN) gamma and interleukin (IL)-17A. Phospho-STAT3–positive CD4(+) T cells correlated with systemic inflammation (C-reactive protein serum levels). Combination of immunohistology and flow cytometry indicated that phospho-STAT3–positive cells were enriched in the peribiliary liver stroma and represented CD4(+) T cells with prominent production of IFN gamma and IL-17A. JAK1/2 inhibitors blocked STAT3 phosphorylation and production of IFN gamma and IL-6, whereas IL-17A was apparently resistant to this inhibition. DISCUSSION: Our results demonstrate systemic and local activation of the IL-6/STAT3 pathway in PSC. Resistance of IL-17A to STAT3-targeted inhibition points to a more complex immune dysregulation beyond STAT3 activation. Wolters Kluwer 2023-06-01 /pmc/articles/PMC10461951/ /pubmed/37256725 http://dx.doi.org/10.14309/ctg.0000000000000603 Text en © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution Licence 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Article
Dold, Leona
Frank, Leonie
Lutz, Philipp
Kaczmarek, Dominik J.
Krämer, Benjamin
Nattermann, Jacob
Weismüller, Tobias J.
Branchi, Vittorio
Toma, Marieta
Gonzalez-Carmona, Maria
Strassburg, Christian P.
Spengler, Ulrich
Langhans, Bettina
IL-6–Dependent STAT3 Activation and Induction of Proinflammatory Cytokines in Primary Sclerosing Cholangitis
title IL-6–Dependent STAT3 Activation and Induction of Proinflammatory Cytokines in Primary Sclerosing Cholangitis
title_full IL-6–Dependent STAT3 Activation and Induction of Proinflammatory Cytokines in Primary Sclerosing Cholangitis
title_fullStr IL-6–Dependent STAT3 Activation and Induction of Proinflammatory Cytokines in Primary Sclerosing Cholangitis
title_full_unstemmed IL-6–Dependent STAT3 Activation and Induction of Proinflammatory Cytokines in Primary Sclerosing Cholangitis
title_short IL-6–Dependent STAT3 Activation and Induction of Proinflammatory Cytokines in Primary Sclerosing Cholangitis
title_sort il-6–dependent stat3 activation and induction of proinflammatory cytokines in primary sclerosing cholangitis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10461951/
https://www.ncbi.nlm.nih.gov/pubmed/37256725
http://dx.doi.org/10.14309/ctg.0000000000000603
work_keys_str_mv AT doldleona il6dependentstat3activationandinductionofproinflammatorycytokinesinprimarysclerosingcholangitis
AT frankleonie il6dependentstat3activationandinductionofproinflammatorycytokinesinprimarysclerosingcholangitis
AT lutzphilipp il6dependentstat3activationandinductionofproinflammatorycytokinesinprimarysclerosingcholangitis
AT kaczmarekdominikj il6dependentstat3activationandinductionofproinflammatorycytokinesinprimarysclerosingcholangitis
AT kramerbenjamin il6dependentstat3activationandinductionofproinflammatorycytokinesinprimarysclerosingcholangitis
AT nattermannjacob il6dependentstat3activationandinductionofproinflammatorycytokinesinprimarysclerosingcholangitis
AT weismullertobiasj il6dependentstat3activationandinductionofproinflammatorycytokinesinprimarysclerosingcholangitis
AT branchivittorio il6dependentstat3activationandinductionofproinflammatorycytokinesinprimarysclerosingcholangitis
AT tomamarieta il6dependentstat3activationandinductionofproinflammatorycytokinesinprimarysclerosingcholangitis
AT gonzalezcarmonamaria il6dependentstat3activationandinductionofproinflammatorycytokinesinprimarysclerosingcholangitis
AT strassburgchristianp il6dependentstat3activationandinductionofproinflammatorycytokinesinprimarysclerosingcholangitis
AT spenglerulrich il6dependentstat3activationandinductionofproinflammatorycytokinesinprimarysclerosingcholangitis
AT langhansbettina il6dependentstat3activationandinductionofproinflammatorycytokinesinprimarysclerosingcholangitis