Intestinal Epithelial Cells Express Immunomodulatory ISG15 During Active Ulcerative Colitis and Crohn's Disease.

Autor: Østvik AE; Department of Clinical and Molecular Medicine, NTNU-Norwegian University of Science and Technology, Trondheim, Norway.; Department of G2astroenterology and Hepatology, Clinic of Medicine, St. Olav's University Hospital, Trondheim, Norway., Svendsen TD; Department of Clinical and Molecular Medicine, NTNU-Norwegian University of Science and Technology, Trondheim, Norway., Granlund AVB; Department of Clinical and Molecular Medicine, NTNU-Norwegian University of Science and Technology, Trondheim, Norway.; Centre of Molecular Inflammation Research, NTNU-Norwegian University of Science and Technology, Trondheim, Norway., Doseth B; Department of Clinical and Molecular Medicine, NTNU-Norwegian University of Science and Technology, Trondheim, Norway., Skovdahl HK; Department of Clinical and Molecular Medicine, NTNU-Norwegian University of Science and Technology, Trondheim, Norway., Bakke I; Department of Clinical and Molecular Medicine, NTNU-Norwegian University of Science and Technology, Trondheim, Norway.; Clinic of Medicine, St Olav's University Hospital, Trondheim, Norway.; Clinic of Laboratory Medicine, St. Olav's University Hospital, Trondheim, Norway., Thorsvik S; Department of Clinical and Molecular Medicine, NTNU-Norwegian University of Science and Technology, Trondheim, Norway.; Department of G2astroenterology and Hepatology, Clinic of Medicine, St. Olav's University Hospital, Trondheim, Norway.; Centre of Molecular Inflammation Research, NTNU-Norwegian University of Science and Technology, Trondheim, Norway., Afroz W; Department of Clinical and Molecular Medicine, NTNU-Norwegian University of Science and Technology, Trondheim, Norway., Walaas GA; Department of Clinical and Molecular Medicine, NTNU-Norwegian University of Science and Technology, Trondheim, Norway., Mollnes TE; Centre of Molecular Inflammation Research, NTNU-Norwegian University of Science and Technology, Trondheim, Norway.; Research Laboratory, Nordland Hospital, Bodo, Norway.; K.G. Jebsen Thrombosis Research and Expertise Center, Institute of Clinical Medicine, University of Tromsø, Tromsø, Norway.; Department of Immunology, Oslo University Hospital and University of Oslo, Oslo, Norway., Gustafsson BI; Department of Clinical and Molecular Medicine, NTNU-Norwegian University of Science and Technology, Trondheim, Norway.; Department of G2astroenterology and Hepatology, Clinic of Medicine, St. Olav's University Hospital, Trondheim, Norway., Sandvik AK; Department of Clinical and Molecular Medicine, NTNU-Norwegian University of Science and Technology, Trondheim, Norway.; Department of G2astroenterology and Hepatology, Clinic of Medicine, St. Olav's University Hospital, Trondheim, Norway.; Centre of Molecular Inflammation Research, NTNU-Norwegian University of Science and Technology, Trondheim, Norway., Bruland T; Department of Clinical and Molecular Medicine, NTNU-Norwegian University of Science and Technology, Trondheim, Norway.; Clinic of Medicine, St Olav's University Hospital, Trondheim, Norway.
Jazyk: angličtina
Zdroj: Journal of Crohn's & colitis [J Crohns Colitis] 2020 Jul 30; Vol. 14 (7), pp. 920-934.
DOI: 10.1093/ecco-jcc/jjaa022
Abstrakt: Background and Aims: Intestinal epithelial cells [IECs] secrete cytokines that recruit immune cells to the mucosa and regulate immune responses that drive inflammation in inflammatory bowel disease [IBD]. However, experiments in patient-derived IEC models are still scarce. Here, we aimed to investigate how innate immunity and IEC-specific pattern recognition receptor [PRR] signalling can be involved in an enhanced type I interferon [IFN] gene signature observed in colon epithelium of patients with active IBD, with a special focus on secreted ubiquitin-like protein ISG15.
Methods: Gene and protein expression in whole mucosa biopsies and in microdissected human colonic epithelial lining, in HT29 human intestinal epithelial cells and primary 3D colonoids treated with PRR-ligands and cytokines, were detected by transcriptomics, in situ hybridisation, immunohistochemistry, western blots, and enzyme-linked immunosorbent assay [ELISA]. Effects of IEC-secreted cytokines were examined in human peripheral blood mononuclear cells [PBMCs] by multiplex chemokine profiling and ELISA.
Results: The type I IFN gene signature in human mucosal biopsies was mimicked in Toll-like receptor TLR3 and to some extent tumour necrosis factor [TNF]-treated human IECs. In intestinal biopsies, ISG15 expression correlated with expression of the newly identified receptor for extracellular ISG15, LFA-1 integrin. ISG15 was expressed and secreted from HT29 cells and primary 3D colonoids through both JAK1-pSTAT-IRF9-dependent and independent pathways. In experiments using PBMCs, we show that ISG15 releases IBD-relevant proinflammatory cytokines such as CXCL1, CXCL5, CXCL8, CCL20, IL1, IL6, TNF, and IFNγ.
Conclusions: ISG15 is secreted from primary IECs upon extracellular stimulation, and mucosal ISG15 emerges as an intriguing candidate for immunotherapy in IBD.
(© European Crohn’s and Colitis Organisation (ECCO) 2020.)
Databáze: MEDLINE
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