Interleukin-2-mediated NF-kB-dependent mRNA splicing modulates interferon gamma protein production

Interferon-gamma (IFNgamma) is a pleiotropic cytokine produced by natural killer (NK) cells during the early infection response. IFNgamma expression is tightly regulated to mount sterilizing immunity while preventing tissue pathology. Several post-transcriptional effectors dampen IFNgamma expression through IFNG mRNA degradation. In this study, we identify mRNA splicing as a positive regulator of IFNgamma production. While treatment with the combination of IL-12 and IL-2 causes synergistic induction of IFNG mRNA and protein, defying transcription-translation kinetics, we observe that NK cells treated with IL-12 alone transcribe IFNG with introns intact. When NK cells are treated with both IL-2 and IL-12, IFNG transcript is spliced to form mature mRNA with a concomitant increase in IFNgamma protein. We find that IL-2-mediated intron splicing occurs independently of nascent transcription but relies upon NF-kB signaling. We propose that while IL-12 transcriptionally induces IFNG mRNA, IL-2 signaling stabilizes IFNG mRNA by splicing detained introns, allowing for rapid IFNgamma protein production. This study uncovers a novel role for cytokine-induced splicing in regulating IFNgamma through a mechanism potentially applicable to other inflammatory mediators. © 2024. The Author(s).

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