Regulation Of Interleukin-2in T Lymphocytes By MCPIP1and The Underlying Mechanism

Interleukin2(IL-2), a key T lymphocytes-derived immunoregulatory cytokine, plays a major role in maintaining lymphocyte homeostasis. IL-2stimulates the activation, survival and proliferation of T lymphocytes in vitro, while its main function in vivo is to limit lymphoid expansion and to promote peripheral tolerance. The absence of IL-2results in the development of lethal autoimmunity and abnormal high level of IL-2impairs the functions of many immune cells. The IL-2mRNA achieves its normal level in the stimulated T lymphocytes by regulating the rate of transcriptional activation and mRNA degradation. The posttranscriptional regulation is via controlling the stability of mRNA. IL-2is known to be regulated by RNA binding proteins, such as tristetraprolin (TTP), via an AU-rich element (ARE) in the3’-untranslated region (3’UTR) to influence the stability of mRNA.The CCCH zinc finger protein MCPIP1(encoded by ZC3H12A gene) is previously known as a negative regulator in the macrophage activation. MCPIP1knockout mice developed a syndrome of severe anemia or severe autoimmune response and most of the mice died within12weeks. Macrophages from MCPIP1knockout mice showed highly increased production of IL-6and IL-12p40in response to TLR ligands. The underlying mechanism is mainly considered that MCPIP1is an essential RNase and down-regulates specific mRNAs of cytokines via a conserved region in the non-ARE of the3’UTR. Here, we reported that MCPIP1was induced in the activation of T lymphocytes and negatively regulated IL-2gene expression in both mouse and human primary T lymphocytes through destabilizing its mRNA. We generated a transgenic mouse model of MCPIP1overexpression, in which MCPIP1was expressed in a T cell-restricted fashion, and we found that IL-2expression of transgenic mouse T cells was much lower than that of wild type mouse T cells. A set of luciferase reporter assay demonstrated that a non-ARE conserved element in IL-23’UTR, which formed a stem-loop structure, responded to MCPIP1activity. RNA immunoprecipitation and Biotin pulldown experiments further suggested that MCPIP1could modestly bind to IL-2mRNA. Taken together, these data demonstrate that MCPIP1down-regulates IL-2via an ARE-independent pathway.