{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T19:08:26Z","timestamp":1790795306777,"version":"4.1.0"},"reference-count":63,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,4,11]],"date-time":"2023-04-11T00:00:00Z","timestamp":1681171200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100008276","name":"Skibsreder Per Henriksen, R. og hustrus fond","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100008276","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>EndoC-\u03b2H5 is a newly established human beta-cell model which may be superior to previous model systems. Exposure of beta cells to pro-inflammatory cytokines is widely used when studying immune-mediated beta-cell failure in type 1 diabetes. We therefore performed an in-depth characterization of the effects of cytokines on EndoC-\u03b2H5 cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The sensitivity profile of EndoC-\u03b2H5 cells to the toxic effects of interleukin-1\u03b2 (IL-1\u03b2), interferon \u03b3 (IFN\u03b3) and tumor necrosis factor-\u03b1 (TNF\u03b1) was examined in titration and time-course experiments. Cell death was evaluated by caspase-3\/7 activity, cytotoxicity, viability, TUNEL assay and immunoblotting. Activation of signaling pathways and major histocompatibility complex (MHC)-I expression were examined by immunoblotting, immunofluorescence, and real-time quantitative PCR (qPCR). Insulin and chemokine secretion were measured by ELISA and Meso Scale Discovery multiplexing electrochemiluminescence, respectively. Mitochondrial function was evaluated by extracellular flux technology. Global gene expression was characterized by stranded RNA sequencing.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Cytokines increased caspase-3\/7 activity and cytotoxicity in EndoC-\u03b2H5 cells in a time- and dose-dependent manner. The proapoptotic effect of cytokines was primarily driven by IFN\u03b3 signal transduction. Cytokine exposure induced MHC-I expression and chemokine production and secretion. Further, cytokines caused impaired mitochondrial function and diminished glucose-stimulated insulin secretion. Finally, we report significant changes to the EndoC-\u03b2H5 transcriptome including upregulation of the human leukocyte antigen (<jats:italic>HLA<\/jats:italic>) genes, endoplasmic reticulum stress markers, and non-coding RNAs, in response to cytokines. Among the differentially expressed genes were several type 1 diabetes risk genes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our study provides detailed insight into the functional and transcriptomic effects of cytokines on EndoC-\u03b2H5 cells. This information should be useful for future studies using this novel beta-cell model.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2023.1128523","type":"journal-article","created":{"date-parts":[[2023,4,11]],"date-time":"2023-04-11T04:49:43Z","timestamp":1681188583000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":22,"title":["Characterization of the functional and transcriptomic effects of pro-inflammatory cytokines on human EndoC-\u03b2H5 beta cells"],"prefix":"10.3389","volume":"14","author":[{"given":"Caroline","family":"Fr\u00f8rup","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebekka","family":"Gerwig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilie Amalie 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