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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^*,1, Atsushi Fujimoto, Naoyuki Tamura^*, Toshiki Yajima^*, Worawidh Wajjwalku and Yasunobu Yoshikai^*

^* Division of Host Defense, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan; and
Laboratory of Host Defense & Germfree Life, Research Institute for Disease Mechanism and Control, Nagoya University School of Medicine, Nagoya, Japan

¹Correspondence: Division of Host Defense, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. E-mail: nishihit{at}bioreg.kyushu-u.ac.jp

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 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 (IL-15R). IL-15 promoter activity was suppressed in the transfected cells. Although nuclear factor-B 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-15R. IL-15 was mainly colocalized with IL-15R at the cytoplasmic membrane of RAW264.7 cells, which had been cotransfected with normal IL-15, whereas nonsecretable IL-15 was colocalized with IL-15R in nucleus after cotransfection with alternative IL-15 and IL-15R. 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.

Key Words: cytokine • gene transcription • negative feedback

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