MCPIP1 down-regulates IL-2 expression through an ARE-independent pathway.

Min Li,Wenqiang Cao,Jing Guo,Xia Liu,Jianli Wang,Hang Zhang,Lie Wang,Wei Zhang,Zhijian Cai,Haifeng Liu,Xuelian Wang,Zhaoyuan Hui,Georg Stoecklin

doi:10.1371/journal.pone.0049841

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.

Highlights

Interleukin 2 (IL-2), a key T lymphocytes-derived immunoregulatory cytokine, plays a major role in maintaining lymphocyte homeostasis [1]
Previous studies have demonstrated that MCPIP1 plays an important role in regulating cytokines in the activation of macrophages through degrading mRNA via a non-AU-rich element (ARE) conserved element within the 39-untranslated region (39UTR) [17]
We tested if MCPIP1 and other members of the MCPIP family were involved in the activation of T lymphocytes

Summary

Introduction

Interleukin 2 (IL-2), a key T lymphocytes-derived immunoregulatory cytokine, plays a major role in maintaining lymphocyte homeostasis [1]. The IL-2 mRNA achieves its normal level in the stimulated T lymphocytes by regulating the rate of transcriptional activation and mRNA degradation. The transcription of IL-2 is regulated mainly through its promoter region, which is the binding site for transcription factors, such as activating protein-1 (AP-1) and NFkB [6]. Tristetraprolin (TTP, known as Zfp36) is one of the most widely studied RNA binding proteins. It was identified as a regulator involved in the turnover of mRNAs of cytokines, such as, TNF-a [9], IL-2 and IL-17 [10,11], in an ARE dependent manner. Hu antigen R (HuR ) and Nuclear factor 90 (NF90) are RNA-binding proteins which bind to IL-2 39UTR but increase its mRNA stability [12,13]

Methods

Results

Conclusion