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Tofacitinib Downregulates TNF and Poly(I:C)-Dependent MHC-II Expression in the Colonic Epithelium

Major Histocompatibility Complex (MHC)-I and -II genes are upregulated in intestinal epithelial cells (IECs) during active inflammatory bowel diseases (IBD), but little is known about how IBD-relevant pro-inflammatory signals and IBD drugs can regulate their expression. We have previously shown that...

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Autores principales: Gopalakrishnan, Shreya, Hansen, Marianne Doré, Skovdahl, Helene Kolstad, Roseth, Ingrid Aass, van Beelen Granlund, Atle, Østvik, Ann Elisabet, Bakke, Ingunn, Sandvik, Arne Kristian, Bruland, Torunn
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9152176/
https://www.ncbi.nlm.nih.gov/pubmed/35655783
http://dx.doi.org/10.3389/fimmu.2022.882277
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author Gopalakrishnan, Shreya
Hansen, Marianne Doré
Skovdahl, Helene Kolstad
Roseth, Ingrid Aass
van Beelen Granlund, Atle
Østvik, Ann Elisabet
Bakke, Ingunn
Sandvik, Arne Kristian
Bruland, Torunn
author_facet Gopalakrishnan, Shreya
Hansen, Marianne Doré
Skovdahl, Helene Kolstad
Roseth, Ingrid Aass
van Beelen Granlund, Atle
Østvik, Ann Elisabet
Bakke, Ingunn
Sandvik, Arne Kristian
Bruland, Torunn
author_sort Gopalakrishnan, Shreya
collection PubMed
description Major Histocompatibility Complex (MHC)-I and -II genes are upregulated in intestinal epithelial cells (IECs) during active inflammatory bowel diseases (IBD), but little is known about how IBD-relevant pro-inflammatory signals and IBD drugs can regulate their expression. We have previously shown that the synthetic analog of double-stranded RNA (dsRNA) Polyinosinic:polycytidylic acid (Poly(I:C)), induces interferon stimulated genes (ISGs) in colon organoids (colonoids). These ISGs may be involved in the induction of antigen presentation. In the present study, we applied colonoids derived from non-IBD controls and ulcerative colitis patients to identify induction and effects of IBD-drugs on antigen presentation in IECs in the context of Tumor Necrosis Factor (TNF)-driven inflammation. By RNA sequencing, we show that a combination of TNF and Poly(I:C) strongly induced antigen-presentation gene signatures in colonoids, including expression of MHC-II genes. MHC-I and -II protein expression was confirmed by immunoblotting and immunofluorescence. TNF+Poly(I:C)-dependent upregulation of MHC-II expression was associated with increased expression of Janus Kinases JAK1/2 as well as increased activation of transcription factor Signal transducer and activator of transcription 1 (STAT1). Accordingly, pre-treatment of colonoids with IBD-approved pan-Janus Kinase (JAK) inhibitor Tofacitinib led to the downregulation of TNF+Poly(I:C)-dependent MHC-II expression associated with the abrogation of STAT1 activation. Pre-treatment with corticosteroid Budesonide, commonly used in IBD, did not alter MHC-II expression. Collectively, our results identify a regulatory role for IBD-relevant pro-inflammatory signals on MHC-II expression that is influenced by Tofacitinib.
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spelling pubmed-91521762022-06-01 Tofacitinib Downregulates TNF and Poly(I:C)-Dependent MHC-II Expression in the Colonic Epithelium Gopalakrishnan, Shreya Hansen, Marianne Doré Skovdahl, Helene Kolstad Roseth, Ingrid Aass van Beelen Granlund, Atle Østvik, Ann Elisabet Bakke, Ingunn Sandvik, Arne Kristian Bruland, Torunn Front Immunol Immunology Major Histocompatibility Complex (MHC)-I and -II genes are upregulated in intestinal epithelial cells (IECs) during active inflammatory bowel diseases (IBD), but little is known about how IBD-relevant pro-inflammatory signals and IBD drugs can regulate their expression. We have previously shown that the synthetic analog of double-stranded RNA (dsRNA) Polyinosinic:polycytidylic acid (Poly(I:C)), induces interferon stimulated genes (ISGs) in colon organoids (colonoids). These ISGs may be involved in the induction of antigen presentation. In the present study, we applied colonoids derived from non-IBD controls and ulcerative colitis patients to identify induction and effects of IBD-drugs on antigen presentation in IECs in the context of Tumor Necrosis Factor (TNF)-driven inflammation. By RNA sequencing, we show that a combination of TNF and Poly(I:C) strongly induced antigen-presentation gene signatures in colonoids, including expression of MHC-II genes. MHC-I and -II protein expression was confirmed by immunoblotting and immunofluorescence. TNF+Poly(I:C)-dependent upregulation of MHC-II expression was associated with increased expression of Janus Kinases JAK1/2 as well as increased activation of transcription factor Signal transducer and activator of transcription 1 (STAT1). Accordingly, pre-treatment of colonoids with IBD-approved pan-Janus Kinase (JAK) inhibitor Tofacitinib led to the downregulation of TNF+Poly(I:C)-dependent MHC-II expression associated with the abrogation of STAT1 activation. Pre-treatment with corticosteroid Budesonide, commonly used in IBD, did not alter MHC-II expression. Collectively, our results identify a regulatory role for IBD-relevant pro-inflammatory signals on MHC-II expression that is influenced by Tofacitinib. Frontiers Media S.A. 2022-05-17 /pmc/articles/PMC9152176/ /pubmed/35655783 http://dx.doi.org/10.3389/fimmu.2022.882277 Text en Copyright © 2022 Gopalakrishnan, Hansen, Skovdahl, Roseth, van Beelen Granlund, Østvik, Bakke, Sandvik and Bruland https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Gopalakrishnan, Shreya
Hansen, Marianne Doré
Skovdahl, Helene Kolstad
Roseth, Ingrid Aass
van Beelen Granlund, Atle
Østvik, Ann Elisabet
Bakke, Ingunn
Sandvik, Arne Kristian
Bruland, Torunn
Tofacitinib Downregulates TNF and Poly(I:C)-Dependent MHC-II Expression in the Colonic Epithelium
title Tofacitinib Downregulates TNF and Poly(I:C)-Dependent MHC-II Expression in the Colonic Epithelium
title_full Tofacitinib Downregulates TNF and Poly(I:C)-Dependent MHC-II Expression in the Colonic Epithelium
title_fullStr Tofacitinib Downregulates TNF and Poly(I:C)-Dependent MHC-II Expression in the Colonic Epithelium
title_full_unstemmed Tofacitinib Downregulates TNF and Poly(I:C)-Dependent MHC-II Expression in the Colonic Epithelium
title_short Tofacitinib Downregulates TNF and Poly(I:C)-Dependent MHC-II Expression in the Colonic Epithelium
title_sort tofacitinib downregulates tnf and poly(i:c)-dependent mhc-ii expression in the colonic epithelium
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9152176/
https://www.ncbi.nlm.nih.gov/pubmed/35655783
http://dx.doi.org/10.3389/fimmu.2022.882277
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