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

ABSTRACT: Interferon-gamma (IFNy) is a pleiotropic cytokine produced by natural killer (NK) cells during the early infection response. IFNy expression is tightly regulated to mount sterilizing immunity while preventing tissue pathology. Several post-transcriptional effectors dampen IFNy expression through IFNG mRNA degradation. In this study, we identify mRNA splicing as a positive regulator of IFNy 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 IFNy protein. We find that IL-2-mediated intron splicing occurs independently of nascent transcription but relies upon NF-κB signaling. We propose that while IL-12 transcriptionally induces IFNG mRNA, IL-2 signaling stabilizes IFNG mRNA by splicing detained introns, allowing for rapid IFN protein production. This study uncovers a novel role for cytokine-induced splicing in regulating IFNy through a mechanism potentially applicable to other inflammatory mediators.

SUBMITTER: Dr. Rachel, D. Van Gelder

PROVIDER: S-SCDT-10_1038-S44319-024-00324-1 | biostudies-other |

REPOSITORIES: biostudies-other

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Project description:PurposeThe aim of this study was to investigate the role of genetic background in determining the development or prognosis of experimental fungal keratitis by comparing the disease courses and related molecules of experimental Candida albicans in two common mouse strains.MethodsAfter intrastromal inoculation of 1 × 10(5)C. albicans blastospores into corneas of Balb/c and C57BL/6 mice, all mice developed typical keratitis. The disease was monitored using a slit lamp microscope and scored for comparison of symptoms. At desired time points, blood was collected and corneal homogenates were prepared for enzyme-linked immunosorbent assay measurement of interferon (IFN)γ or interleukin (IL)17. Other corneas were processed for histological evaluation, pathogen load measurement, or total RNA extraction, the last of which was subjected to reverse transcription in conjunction with real-time PCR to measure genes of interest in terms of collagens, matrix metalloproteinases (MMPs), and the tissue inhibitors of MMPs (TIMPs).ResultsThe infected corneas from the two strains presented different manifestations. Corneal transparency was less affected in Balb/c mice than in C57BL/6 mice, and Balb/c corneas contained fewer pathogens than C57BL/6 corneas during the measured period (10 days). In both strains, keratitis started to resolve around days 7-10, but C57BL/6 mice healed slower than Balb/c mice as indicated by disease presentation, histology, and pathogen burden assay. By day 7 post infection, pseudohyphae were rare but cellular infiltration remained intensive in both strains. The surface of the Balb/c corneas remained relatively intact and smooth, and C57BL/6 corneal lesions produced open erosion areas. Perforation was never seen in the current study setting. In both sera and corneas, IL17 expression increased earlier than IFNγ, and C57BL/6 mice produced higher IL17 levels and lower IFNγ levels than Balb/c mice. Compared with C57BL/6 mice, Balb/c corneas produced more MMP-2, Col3a1, and Col4a1, and less or equivalent TIMP-2 at all detected time points. They also produced more MMP-13, less MMP-8, MMP-9, and TIMP-1 at day 3 post infection, but less MMP-13, basically equivalent MMP-8, and more MMP-9 at later time points.ConclusionsThe disease course of experimental C. albicans keratitis depends on the genetic background of the host animals. The balance between IL17 and IFNγ, as well as among the common injury- and wound healing-related proteins, may contribute to the pathogenesis of C. albicans keratitis. This study suggests that great variance of disease presentation should be expected for human subjects with Candida keratitis.

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

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