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

Autor:	Gopalakrishnan S; Department of Clinical and Molecular Medicine (IKOM), NTNU - Norwegian University of Science and Technology, Trondheim, Norway.; Department of Gastroenterology and Hepatology, Clinic of Medicine, St. Olav's University Hospital, Trondheim, Norway., Hansen MD; Department of Clinical and Molecular Medicine (IKOM), NTNU - Norwegian University of Science and Technology, Trondheim, Norway.; Clinic of Laboratory Medicine, St. Olav's University Hospital, Trondheim, Norway., Skovdahl HK; Department of Clinical and Molecular Medicine (IKOM), NTNU - Norwegian University of Science and Technology, Trondheim, Norway.; Centre of Molecular Inflammation Research (CEMIR), NTNU - Norwegian University of Science and Technology, Trondheim, Norway., Roseth IA; Department of Clinical and Molecular Medicine (IKOM), NTNU - Norwegian University of Science and Technology, Trondheim, Norway., van Beelen Granlund A; Department of Clinical and Molecular Medicine (IKOM), NTNU - Norwegian University of Science and Technology, Trondheim, Norway.; Department of Gastroenterology and Hepatology, Clinic of Medicine, St. Olav's University Hospital, Trondheim, Norway.; Centre of Molecular Inflammation Research (CEMIR), NTNU - Norwegian University of Science and Technology, Trondheim, Norway., Østvik AE; Department of Clinical and Molecular Medicine (IKOM), NTNU - Norwegian University of Science and Technology, Trondheim, Norway.; Department of Gastroenterology and Hepatology, Clinic of Medicine, St. Olav's University Hospital, Trondheim, Norway., Bakke I; Department of Clinical and Molecular Medicine (IKOM), NTNU - Norwegian University of Science and Technology, Trondheim, Norway.; Clinic of Laboratory Medicine, St. Olav's University Hospital, Trondheim, Norway., Sandvik AK; Department of Clinical and Molecular Medicine (IKOM), NTNU - Norwegian University of Science and Technology, Trondheim, Norway.; Department of Gastroenterology and Hepatology, Clinic of Medicine, St. Olav's University Hospital, Trondheim, Norway.; Centre of Molecular Inflammation Research (CEMIR), NTNU - Norwegian University of Science and Technology, Trondheim, Norway., Bruland T; Department of Clinical and Molecular Medicine (IKOM), NTNU - Norwegian University of Science and Technology, Trondheim, Norway.; Department of Gastroenterology and Hepatology, Clinic of Medicine, St. Olav's University Hospital, Trondheim, Norway.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2022 May 17; Vol. 13, pp. 882277. Date of Electronic Publication: 2022 May 17 (Print Publication: 2022).
DOI:	10.3389/fimmu.2022.882277
Abstrakt:	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. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2022 Gopalakrishnan, Hansen, Skovdahl, Roseth, van Beelen Granlund, Østvik, Bakke, Sandvik and Bruland.)
Databáze:	MEDLINE
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