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Journal of Interferon & Cytokine Research

Tristetraprolin Regulates Interleukin-6 Expression Through p38 MAPK-Dependent Affinity Changes with mRNA 3′ Untranslated Region

To cite this article:
Wenpu Zhao, Min Liu, Nisha J. D'Silva, and Keith L. Kirkwood. Journal of Interferon & Cytokine Research. August 2011, 31(8): 629-637. https://doi.org/10.1089/jir.2010.0154

Published in Volume: 31 Issue 8: August 8, 2011
Online Ahead of Print: April 3, 2011

Author information

Wenpu Zhao,1 Min Liu,1 Nisha J. D'Silva,1,2 and Keith L. Kirkwood3
1Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan.
2Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
3Department of Craniofacial Biology and Microbiology and Immunology, Center for Oral Health Research, Medical University of South Carolina, Charleston, South Carolina.
Address correspondence to:
Dr. Keith L. Kirkwood
Department of Craniofacial Biology and Microbiology and Immunology
Center for Oral Health Research
Medical University of South Carolina
173 Ashley Ave.
Charleston, SC 29425
E-mail:
Received 2 December 2010
Accepted 17 February 2011

ABSTRACT

Tristetraprolin (TTP) is a well-characterized, zinc finger-containing, RNA-binding protein. TTP targets tumor necrosis factor α for degradation via the 3′ untranslated region (3′UTR). Although AU-rich elements (AREs) in the 3′UTR of interleukin-6 (IL-6) mRNA dictate mRNA degradation, the role of TTP in the post-transcriptional regulation of IL-6 gene expression is unclear. Here we used TTP-deficient mice to test the hypothesis that IL-6 expression is influenced by TTP. Genetic and siRNA-mediated knockdown of TTP resulted in increased IL-6 production and overexpression of TTP had the reverse effect. IL-6 and tumor necrosis factor α production were elevated after injection of IL-1β in TTP-deficient mice. Further, embryonic fibroblasts from these mice (mouse embryonic fibroblasts) exhibited greater IL-6 mRNA expression and longer half-life than wild-type mouse embryonic fibroblasts. Overexpression of TTP reduced IL-6 3′UTR luciferase reporter activity in an ARE-dependent manner. Proximal and distal regions of the 3′UTR acted synergistically to produce the full repression of TTP. Mutation-based luciferase assays show that ARE2, ARE3, and ARE4 are required for TTP-mediated repression. The constitutively activated p38-MK2 pathway abrogated TTP-mediated repression of IL-6 3′UTR reporter activity. RNA immunoprecipitation assay indicated that the deficiency of p38α resulted in the increased affinity of TTP to IL-6 mRNA. Taken together, we propose that TTP downregulates IL-6 gene expression at the post-transcriptional level by targeting ARE elements in the 3′UTR region.

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