Tristetraprolin down-regulates IL-2 gene expression through AU-rich element-mediated mRNA decay

Rachel L. Ogilvie, Michelle Abelson, Heidi H. Hau, Irina Vlasova, Perry J. Blackshear, Paul R. Bohjanen

Research output: Contribution to journalArticle

145 Scopus citations

Abstract

Posttranscriptional regulation of IL-2 gene expression at the level of mRNA decay is mediated by an AU-rich element (ARE) found in the 3′- untranslated region. We hypothesized that the ARE-binding protein tristetraprolin (TTP) regulates T lymphocyte IL-2 mRNA decay by interacting with the IL-2 ARE and targeting the transcript for decay. rTTP protein expressed in HeLa cells bound specifically to the EL-2 ARE with high affinity in a gel shift assay. In primary human T lymphocytes, TTP mRNA and protein expression were induced by TCR and CD28 coreceptor stimulation. Using a gel shift assay, we identified a cytoplasmic RNA-binding activity that was induced by TCR and CD28 coreceptor stimulation and bound specifically to the EL-2 ARE sequence. Using anti-TTP Abs, we showed by supershift that this inducible activity contained TTP. We also showed that insertion of the IL-2 ARE sequence into the 3′-untranslated region of a β-globin reporter construct conferred TTP-dependent mRNA destabilizalion on the β-globin reporter. To determine whether TTP also regulates IL-2 gene expression in vivo, we examined IL-2 expression in primary cells from wild-type and TTP knockout mice. Compared with their wild-type counterparts, TCR- and CD28-activated splenocytes and T cells from TTP knockout mice overexpressed IL-2 mRNA and protein. Also, IL-2 mRNA was more stable in activated splenocytes from TTP knockout mice compared with wild-type mice. Taken together, these data suggest that TTP functions to down-regulate IL-2 gene expression through ARE-mediated mRNA decay.

Original languageEnglish (US)
Pages (from-to)953-961
Number of pages9
JournalJournal of Immunology
Volume174
Issue number2
DOIs
StatePublished - Jan 15 2005

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