Journal
CYTOKINE
Volume 56, Issue 2, Pages 245-255Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.cyto.2011.06.006
Keywords
MKP-1; AUF1; TTP; Cytokine; mRNA
Funding
- National Institutes of Health (NIH) [1R01DE018290, 2P20 RR017696, R00DE018165, T32 DE017551]
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MAPK phosphatase-1 (MKP-1)/dual specificity protein phosphatase-1 (DUSP-1) is a negative regulator of the host inflammatory response to infection. However, the mechanisms underlying the regulation of cytokine expression by MKP-1, especially at the post-transcriptional level, have not been fully delineated. In the current study, MKP-1 specifically dephosphorylated activated MAPK responses and attenuated LPS-induced IL-6, IL-10, and TNF-alpha. expression. In addition, MKP-1 was important in destabilizing cytokine mRNAs. In LPS-stimulated rat macrophages with overexpressed MKP-1, half-lives of IL-6, IL-10 and TNF-alpha mRNAs were significantly reduced compared to controls. Conversely, half-lives of IL-6, IL-10, and TNF-alpha mRNAs were significantly increased in bone marrow macrophages derived from MKP-1 knock out (KO) mice compared with macrophages derived from MKP-1 wild type (WT) mice. Furthermore, MKP-1 promoted translocation of RNA-binding protein (RNA-BP) ARE/poly-(U) binding degradation factor 1 (AUF1) from the nucleus to the cytoplasm in response to LPS stimulation as evidenced by Western blot and immunofluorescent staining. Knockdown AUF1 mRNA expression by AUF1 siRNA in MKP-1 WT bone marrow macrophages significantly delayed degradation of IL-6, IL-10 and TNF-alpha mRNAs compared with controls. Finally, AUF1 was immunoprecipitated with the RNA complex in cellular lysates derived from bone marrow macrophages of MKP-1 KO vs. WT mice, which had increased AUF1-bound target mRNAs, including IL-6, IL-10, and TNF-alpha in WT macrophages compared with MKP-1 KO macrophages. Thus, this work provides new mechanistic insight of MKP-1 signaling and regulation of cytokine mRNA stability through RNA binding proteins in response to inflammatory stimuli. (C) 2011 Elsevier Ltd. All rights reserved.
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