RRC ID 42287
Author Nishimura H, Fujimoto A, Tamura N, Yajima T, Wajjwalku W, Yoshikai Y.
Title A novel autoregulatory mechanism for transcriptional activation of the IL-15 gene by a nonsecretable isoform of IL-15 generated by alternative splicing.
Journal FASEB J
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 alpha 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 alpha (IL-15Ralpha). IL-15 promoter activity was suppressed in the transfected cells. Although nuclear factor-kappaB 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-15Ralpha. IL-15 was mainly colocalized with IL-15Ralpha at the cytoplasmic membrane of RAW264.7 cells, which had been cotransfected with normal IL-15, whereas nonsecretable IL-15 was colocalized with IL-15Ralpha in nucleus after cotransfection with alternative IL-15 and IL-15Ralpha. 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.
Volume 19(1)
Pages 19-28
Published 2005-1-1
DOI 10.1096/fj.04-2633com
PII 19/1/19
PMID 15629891
MeSH Alternative Splicing / genetics* Animals Cell Line DNA / metabolism DNA-Binding Proteins / metabolism Gene Expression Regulation / genetics Homeostasis / genetics* Interleukin-15 / genetics* Interleukin-15 / metabolism* Intracellular Space / chemistry Macrophages / chemistry Macrophages / metabolism Mice Promoter Regions, Genetic / genetics Protein Isoforms / genetics Protein Isoforms / metabolism Receptors, Immunologic / metabolism Receptors, Interleukin-15 Receptors, Interleukin-2 Signal Transduction / genetics Toll-Like Receptor 4 Transcriptional Activation / genetics*
IF 4.966
Times Cited 39
Human and Animal Cells RAW 264(RCB0535)