A novel autoregulatory mechanism for transcriptional activation of the IL-15 gene by a nonsecretable isoform of IL-15 generated by alternative splicing

Hitoshi Nishimura, Atsushi Fujimoto, Naoyuki Tamura, Toshiki Yajima, Worawidh Wajjwalku, Yasunobu Yoshikai

    Research output: Contribution to journalArticlepeer-review

    42 Citations (Scopus)

    Abstract

    There are several isoforms of interleukin (IL) -15 generated by alternating splicing. We reported previously that alternative IL-15 transgenic (Tg) mice expressing an IL-15 cDNA isoform encoding nonsecretable IL-15 protein had an impaired ability to produce IL-15. In this study, we found that expression of endogenous IL-15 mRNA but not tumor necrosis factor α mRNA was severely impaired in response to lipopolysaccharide, not only in macrophages from alternative IL-15 Tg mice but also in RAW264.7 cells that had been transfected with alternative IL-15 together with IL-15 receptor α (IL-15Rα). IL-15 promoter activity was suppressed in the transfected cells. Although nuclear factor-κB activation was not impaired, the binding activity of nuclear extracts to the interferon-stimulated response element of the IL-15 promoter region was reduced in RAW264.7 cells, which had been cotransfected with alternative IL-15 and IL-15Rα. IL-15 was mainly colocalized with IL-15Rα at the cytoplasmic membrane of RAW264.7 cells, which had been cotransfected with normal IL-15, whereas nonsecretable IL-15 was colocalized with IL-15Rα in nucleus after cotransfection with alternative IL-15 and IL-15Rα. These results suggest that nonsecretable IL-15 generated by alternative splicing suppresses further IL-15 gene transcription, implying a novel autocrine regulatory mechanism for cytokine gene expression by alternative splicing.

    Original languageEnglish
    Pages (from-to)19-28
    Number of pages10
    JournalFASEB Journal
    Volume19
    Issue number1
    DOIs
    Publication statusPublished - Jan 2005

    All Science Journal Classification (ASJC) codes

    • Biotechnology
    • Biochemistry
    • Molecular Biology
    • Genetics

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