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IFN\u03b3 expression is tightly regulated to mount sterilizing immunity while preventing tissue pathology. Several post-transcriptional effectors dampen IFN\u03b3 expression through\n                    <jats:italic>IFNG<\/jats:italic>\n                    mRNA degradation. In this study, we identify mRNA splicing as a positive regulator of IFN\u03b3 production. While treatment with the combination of IL-12 and IL-2 causes synergistic induction of\n                    <jats:italic>IFNG<\/jats:italic>\n                    mRNA and protein, defying transcription-translation kinetics, we observe that NK cells treated with IL-12 alone transcribe\n                    <jats:italic>IFNG<\/jats:italic>\n                    with introns intact. When NK cells are treated with both IL-2 and IL-12,\n                    <jats:italic>IFNG<\/jats:italic>\n                    transcript is spliced to form mature mRNA with a concomitant increase in IFN\u03b3 protein. We find that IL-2-mediated intron splicing occurs independently of nascent transcription but relies upon NF-\u03baB signaling. We propose that while IL-12 transcriptionally induces\n                    <jats:italic>IFNG<\/jats:italic>\n                    mRNA, IL-2 signaling stabilizes\n                    <jats:italic>IFNG<\/jats:italic>\n                    mRNA by splicing detained introns, allowing for rapid IFN\u03b3 protein production. This study uncovers a novel role for cytokine-induced splicing in regulating IFN\u03b3 through a mechanism potentially applicable to other inflammatory mediators.\n                  <\/jats:p>","DOI":"10.1038\/s44319-024-00324-1","type":"journal-article","created":{"date-parts":[[2024,11,22]],"date-time":"2024-11-22T09:01:54Z","timestamp":1732266114000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Interleukin-2-mediated NF-\u03baB-dependent mRNA splicing modulates interferon gamma protein production"],"prefix":"10.1038","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1941-6244","authenticated-orcid":false,"given":"Rachel D","family":"Van Gelder","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nandan S","family":"Gokhale","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuelle","family":"Genoyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dylan S","family":"Omelia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7856-4266","authenticated-orcid":false,"given":"Stephen K","family":"Anderson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3118-5111","authenticated-orcid":false,"given":"Howard A","family":"Young","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3087-1355","authenticated-orcid":false,"given":"Ram","family":"Savan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,11,22]]},"reference":[{"key":"324_CR1","first-page":"355","volume":"6","author":"AK Ali","year":"2015","unstructured":"Ali AK, Nandagopal N, Lee S-H (2015) IL-15\u2013PI3K\u2013AKT\u2013mTOR: a critical pathway in the life journey of natural killer cells. 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