MCPIP1 Down-Regulates IL-2 Expression Through an ARE-independent Pathway

PLoS One. 2012;7(11):e49841. doi: 10.1371/journal.pone.0049841. Epub 2012 Nov 21.

Abstract

IL-2 plays a key role in the survival and proliferation of immune cells, especially T lymphocytes. Its expression is precisely regulated at transcriptional and posttranscriptional level. IL-2 is known to be regulated by RNA binding proteins, such as tristetraprolin (TTP), via an AU-rich element (ARE) in the 3'-untranslated region (3'UTR) to influence the stability of mRNA. MCPIP1, identified as a novel RNase, can degrade IL-6, IL-12 and TNF-α mRNA by an ARE-independent pathway in the activation of macrophages. Here, we reported that MCPIP1 was induced in the activation of T lymphocytes and negatively regulated IL-2 gene expression in both mouse and human primary T lymphocytes through destabilizing its mRNA. A set of Luciferase reporter assay demonstrated that a non-ARE conserved element in IL-2 3'UTR, which formed a stem-loop structure, responded to MCPIP1 activity.RNA immunoprecipitation and Biotin pulldown experiments further suggested that MCPIP1 could modestly bind to IL-2 mRNA. Taken together, these data demonstrate that MCPIP1 down-regulates IL-2 via an ARE-independent pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / genetics
  • AU Rich Elements / genetics*
  • Animals
  • Cell Line
  • Gene Expression Regulation
  • Humans
  • Interleukin-12 / metabolism
  • Interleukin-2* / genetics
  • Interleukin-2* / metabolism
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism
  • Mice
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA-Binding Proteins / genetics
  • Ribonucleases
  • T-Lymphocytes / metabolism
  • Transcription Factors* / genetics
  • Transcription Factors* / metabolism
  • Tristetraprolin / metabolism
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • 3' Untranslated Regions
  • Interleukin-2
  • Interleukin-6
  • RNA, Messenger
  • RNA-Binding Proteins
  • Transcription Factors
  • Tristetraprolin
  • Tumor Necrosis Factor-alpha
  • Interleukin-12
  • Ribonucleases
  • ZC3H12A protein, human

Grant support

This work was supported by grants from the National Natural Science Foundation of China (J20111945), National Basic Research Program of China (973 Program) (2012CB966603), Natural Science Foundation of Zhejiang Province, China (R20110298), Doctoral Fund of Ministry of Education of China (20110101120102), the Fundamental Research Funds for the Central Universities (2011QNA7001) and the National Technology Key Projects of China (008ZX1002-008). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.